Decarboxylative conjugate additions and applications thereof

ABSTRACT

Synthetic methods are described herein operable to efficiently produce a wide variety of molecular species through conjugate additions via decarboxylative mechanisms. For example, methods of functionalization of peptide residues are described, including selective functionalization of peptide C-terminal residues. In one aspect, a method of peptide functionalization comprises providing a reaction mixture including a Michael acceptor and a peptide and coupling the Michael acceptor with the peptide via a mechanism including decarboxylation of a peptide reside.

RELATED APPLICATION DATA

This application is a U.S. National Phase of PCT/US2016/035716, filedJun. 3, 2016, which claims priority pursuant to 35 U.S.C. § 119(e)(1) toUnited States Provisional Patent Application Ser. No. 62/171,722 filedJun. 5, 2015, each of which are hereby incorporated by reference intheir entireties.

STATEMENT OF GOVERNMENT RIGHTS

This invention was made with government support under Grant No. GM103558awarded by the National Institutes of Health (NIGMS). The government hascertain rights in the invention.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Feb. 1, 2021, isnamed 060017-00091_SL.txt and is 14,971 bytes in size.

FIELD

The present invention relates to conjugate additions and, in particular,to conjugate additions via decarboxylative mechanisms employingphotoredox catalyst.

BACKGROUND

Molecular synthesis plays a critical role in a significant number ofindustries including the pharmaceutical, biological, biochemical andmaterials industries. Substantial resources and time are invested in theconstruction and development of molecular libraries for thecharacterization and identification of molecular species havingcommercial promise as intermediates or final products for particularapplications. Such libraries, however, are often rendered incomplete bythe inability to efficiently synthesize a wide variety of chemicalspecies. Many classes of chemical species, for example, requireexpensive reagents, complex and time consuming synthetic pathways and/orresult in the production of hazardous by-products. Further, somechemical species cannot be synthesized by current technologies. Forexample, synthetic pathways are not currently available for performingselective chemistries on the C-terminus of proteins in the presence ofall other naturally occurring protein functionalities. In view of thesedeficiencies, new synthetic mutes are required.

SUMMARY

Synthetic methods are described herein operable to efficiently produce awide variety of molecular species through conjugate additions viadecarboxylative mechanisms. For example, methods of functionalization ofpeptide residues are described, including selective functionalization ofpeptide C-terminal residues. In one aspect, a method of peptidefunctionalization comprises providing a reaction mixture including aMichael acceptor and a peptide and coupling the Michael acceptor withthe peptide via a mechanism including decarboxylation of a peptidereside. In some embodiments, the peptide C-terminal residue undergoesdecarboxylative coupling with the Michael acceptor. Alternatively, aninterior residue or non-terminal residue comprising an carboxyl sidechain can undergo decarboxylative coupling with the Michael acceptor. Asdescribed further herein, the resulting coupling product can be a1,4-addition adduct comprising the peptide and a Michael acceptorresidue coupled to a decarboxylated amino acid residue of the peptide.

In another aspect, a method of peptide coupling comprises providing areaction mixture including a first peptide and a second peptide, thesecond peptide comprising a Michael acceptor functionalized N-terminalresidue and coupling the functionalized N-terminal residue with thefirst peptide via a mechanism including decarboxylation of a residue ofthe first peptide. In some embodiments, the first peptide C-terminalresidue undergoes decarboxylative coupling with the Michael acceptorfunctionalized N-terminal residue of the second peptide. In otherembodiments, an interior amino acid residue of the first peptideundergoes decarboxylative coupling with the Michael acceptorfunctionalized N-terminal residue of the second peptide.

In a further aspect, methods of intramolecular peptide cyclization aredescribed herein. For example, a method of intramolecular peptidecyclization comprises providing a reaction mixture comprising a peptideincluding a C-terminal residue and a Michael acceptor functionalizedN-terminal residue and coupling the C-terminal residue with thefunctionalized N-terminal residue via a mechanism includingdecarboxylation of the C-terminal residue. Coupling of the Michaelacceptor functionalized N-terminal residue with the C-terminal residueresults in cyclization of the peptide.

Moreover, general methods of conjugate addition are also describedherein. A method of conjugate addition comprises providing a reactionmixture including a Michael acceptor and a substrate having a carboxylgroup and coupling the Michael acceptor and substrate via a mechanismincluding decarboxylation of the substrate.

These and other embodiments are further described in the followingdetailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates various Michael acceptors according to someembodiments described herein.

FIG. 2 illustrates peptide functionalization at the C-terminal residueaccording to some embodiments described herein.

FIG. 3 illustrates peptide functionalization at the C-terminal residueaccording to some embodiments described herein. Figure discloses SEQ IDNOS 38-41, respectively, in order of appearance.

FIG. 4 illustrates peptide functionalization at the C-terminal residueaccording to some embodiments described herein. Figure discloses SEQ IDNOS 42-43, 1, and 44-45, respectively, in order of appearance.

FIGS. 5A-5E illustrate examples of C-terminus peptide functionalizationunder various reaction conditions according to some embodimentsdescribed herein.

FIGS. 6A-6C illustrate various Michael acceptors for peptidefunctionalization at the C-terminus under differing catalyst conditionsaccording to some embodiments described herein.

FIGS. 7A-7C illustrate peptide functionalization at interior locationsvia decarboxylative mechanisms described herein. FIG. 7A discloses SEQID NOS 46-52, respectively, in order of appearance.

FIG. 8 illustrates an example of peptide coupling according to oneembodiment of a method described herein. Figure discloses SEQ ID NOS2-3, respectively, in order of appearance.

FIG. 9 illustrates a mechanistic pathway of peptide intramolecularcyclization via decarboxylation according to one example of a methoddescribed herein.

FIG. 10 illustrates a mechanistic pathway wherein thiol co-catalyst isemployed for hydrogen atom transfer to an acyl radical according to someembodiments described herein.

FIG. 11 illustrates an example of peptide intramolecular cyclizationaccording to one embodiment of a method described herein. Figurediscloses SEQ ID NO: 53.

FIG. 12 illustrates various carboxylic acid substrates according to someembodiments described herein.

FIG. 13 illustrates a mechanistic pathway of conjugate addition viadecarboxylation according to one example of a method described herein.

DETAILED DESCRIPTION

Embodiments described herein can be understood more readily by referenceto the following detailed description and examples and their previousand following descriptions. Elements, apparatus and methods describedherein, however, are not limited to the specific embodiments presentedin the detailed description and examples. It should be recognized thatthese embodiments are merely illustrative of the principles of thepresent invention. Numerous modifications and adaptations will bereadily apparent to those of skill in the art without departing from thespirit and scope of the invention.

Definitions

The term “alkyl” as used herein, alone or in combination, refers to astraight or branched saturated hydrocarbon group. For example, an alkylcan be C₁-C₃₀.

The term “alkenyl” as used herein, alone or in combination, refers to astraight or branched chain hydrocarbon group having at least onecarbon-carbon double bond.

The term “aryl” as used herein, alone or in combination, refers to anaromatic monocyclic or multicyclic ring system optionally substitutedwith one or more ring substituents

The term “cycloalkyl” as used herein, alone or in combination, refers toa non-aromatic, saturated mono- or multicyclic ring system optionallysubstituted with one or more ring substituents.

The term “cycloalkenyl” as used herein, alone or in combination, refersto a non-aromatic, mono- or muticyclic ring system having at least onecarbon-carbon double bond and is optionally substituted with one or morering substituents.

The term “heterocycloalkyl” as used herein, alone or in combination,refers to a non-aromatic, saturated mono- or multicyclic ring system inwhich one or more of the atoms in the ring system is an element otherthan carbon, such as nitrogen, oxygen or sulfur, alone or incombination, and wherein the ring system is optionally substituted withone or more ring substituents.

The term “heterocycloalkenyl” as used herein, alone or in combination,refers to a non-aromatic, mono- or multicyclic ring system in which oneor more of the atoms in the ring system is an element other than carbon,such as nitrogen, oxygen or sulfur, alone or in combination, and whichcontains at least one carbon-carbon double bond in the ring system andwherein the ring system is optionally substituted with one or more ringsubstituents.

The term “heteroalkyl” as used herein, alone or in combination, refersto an alkyl moiety as defined above, having one or more carbon atoms,for example one, two or three carbon atoms, replaced with one or moreheteroatoms, which may be the same or different.

I. Decarboxylative Peptide Functionalization

Various methods of peptide functionalization via decarboxylativepathways are described herein. In one aspect, a method of peptidefunctionalization comprises providing a reaction mixture including aMichael acceptor and a peptide and coupling the Michael acceptor withthe peptide via a mechanism including decarboxylation of a peptidereside. In some embodiments, the peptide C-terminal residue undergoesdecarboxylative coupling with the Michael acceptor. Alternatively, aninterior residue comprising a carboxyl side chain can undergodecarboxylative coupling with the Michael acceptor. As described furtherherein, the resulting coupling product can be a 1,4-addition adductcomprising the peptide and a Michael acceptor residue coupled to adecarboxylated amino acid residue of the peptide. Additionally, thereaction mixture can further comprise a base component.

A. Peptide

Turning now to specific components, the reaction mixture comprises apeptide. The peptide can have any desired number of amino acids notinconsistent with the objectives of the present invention. In someembodiments, for example, the peptide comprises a number of amino acidsselected form Table I.

TABLE I Number of Amino Acids in Peptide ≥3 ≥5 ≥7 ≥10 ≥15 3-300 5-50010-400 As set forth in Table I, the peptide can comprise a sufficient number ofamino acids to classify as a protein. In some embodiments, the peptidecan comprise one or more β-amino acids in addition to α-amino acids. Thepeptide may also comprise unnatural amino acids and/or amino acidderivatives. In some embodiments, for example, the peptide can containN-methyl amino acid(s) and/or amino acid derivatives comprising carboxylside chains. Table II provides several non-limiting examples ofunnatural amino acids and/or amino acid derivatives.

TABLE II Unnatural Amino Acids or Derivatives γ-aminobutyric acid2-phenyl-γ-aminobutyric acid 4-isobutyl-γ-aminobutyric acid N-methylamino acid L-propargylglycine 1-aminocyclopropane-1-carboxylic acid1-aminocyclopentane-1-carboxylic acid 4-bromo-phenylalanineN-α-Fmoc-N-ω,N-ω-bis-tert-butoxycarbonyl-arginine 4-aminoheptanedioicacid 3-(1-aminocyclopropyl)propanoic acid3-(1-aminocyclopentyl)propanoic acidThe peptide can employ any amino acid or amino acid derivative operableto participate in decarboxylative pathways described herein. In someembodiments, the amino acid residue participating in the decarboxylativepathway is located at the C-terminus. For example, one or more of theamino acids listed in Table III may serve as the C-terminal residue ofthe peptide.

TABLE III Alanine Arginine Asparagine Aspartic Acid Cysteine GlutamicAcid Glutamine Glycine Histidine Isoleucine Leucine Lysine MethioninePhenylalanine Proline Serine Threonine Tryptophan Tyrosine ValineThe carboxyl group of an amino acid residue participating indecarboxylative pathways described herein can be in protonated form,deprotonated form, carboxylate salt, carboxylate ester or otherderivative form.B. Michael Acceptor

As described herein, the reaction mixture also comprises a Michaelacceptor. Michael acceptors operable for use in the present methods canexhibit a number of functional groups including esters, ketones,aldehydes, sulfones, imides, amides and carboxylic acids. For example,the Michael acceptor can be selected from cyclic or acyclic ketones,acyclic enals, α,β-unsaturated imides, sulfones, malonates, acrylatesand maleates. In some embodiments, the Michael acceptor can generally beof formula (I):

wherein EWG is an electron withdrawing group selected from the groupconsisting of -formyl, -keto, -ester, -cyano, -imide, -amide and-sulfone and R¹ and R² are independently selected from the groupconsisting of -hydrogen, -alkyl, -cycloalkyl, -aryl, -alkyl-aryl and-ester. FIG. 1 illustrates various Michael acceptors according to someembodiments described herein.C. Catalyst

The reaction mixture can also include one or more catalytic species toassist in decarboxylative couplings described herein. Catalytic species,in some embodiments, participate in forming a carboxyl radical on aresidue which then rapidly extrudes CO₂ to produce an amino radical. Theamino radical is subsequently operable to undergo conjugate additionwith the Michael acceptor to forge a new C—C bond. Catalyst canparticipate in carboxyl radical formation via a single electron transfer(SET) process. For example, catalyst can act in an oxidative capacity toproduce the carboxyl radical followed by CO₂ extrusion, as illustratedin the non-limiting embodiment of FIG. 9. Alternatively, catalyst canact in reductive capacity to produce the carboxyl radical followed byCO₂ extrusion. Any catalyst operable to initiate a residue carboxylradical followed by CO₂ extrusion is contemplated herein. In someembodiments, catalyst can also close the redox cycle by single electrontransfer (SET) to the acyl radical formed by the conjugate addition, asillustrated in the non-limiting embodiment of FIG. 9. In someembodiments, the catalytic species initiating carboxyl radical formationcan also close the redox cycle by SET. In other embodiments, differentcatalytic species or co-catalysts are used for carboxyl radicalformation and acyl radical reduction.

Various transition metal catalysts may be operable to participate in theforegoing decarboxylative mechanisms and associated SET and/or redoxprocesses. Nickel catalyst and/or noble metal catalyst, for example, maybe suitable for use in coupling methods described herein. In someembodiments, catalyst is photoredox catalyst. Any photoredox catalystoperable to participate in in decarboxylative mechanisms describedherein can be used in the reaction mixture. For example, photoredoxcatalyst can include one or more iridium and/or ruthenium complexes. Insome embodiments, heteroleptic iridium complexes are selected as thephotocatalyst. Suitable heteroleptic iridium complexes can includeIr[dF(CF₃)ppy]2(dtbbpy)⁺, Ir(dF(CF₃)ppy)₂ (4,4′-dcbpy) andIr(ppy)₂(dtbbpy)⁺. Homoleptic iridium complexes, such as Ir(dFppy)₃, canalso be used as photocatalyst.

In other embodiments, photoredox catalyst can comprise one or moreorganic species including, but not limited to, riboflavin derivatives.For example, riboflavin tetrabutyrate or riboflavintetra-N-ethylcarbamate may be employed as photoredox catalyst.

Photoredox catalyst can be present in the reaction mixture in any amountnot inconsistent with the objectives of the present invention. In someembodiments, photoredox catalyst is present in the reaction mixture inan amount selected from Table IV.

TABLE IV Photoredox Catalyst in Reaction Mixture mol. % 0.1-60 0.1-300.1-15 0.1-5  0.5-3  0.5-2 

In further embodiments, one or more electrochemical methods may be usedto initiate carboxyl radical formation and/or acyl radical reduction.For example, one or more electrodes can be positioned in the reactionmixture to initiate decarboxylative mechanisms and associated SET and/orredox processes described herein. Additionally, one or more reducingmetals such as zinc may be used to initiate carboxyl radical formationand/or acyl radical reduction.

D. Base and Solvent Components

In some embodiments, the reaction mixture further comprises base. Anybase not inconsistent with the objectives of the present invention canbe used, including inorganic bases. In some embodiments, suitableinorganic base is selected from Table V.

TABLE V Base of the Reaction Mixture CsF Cs₂CO₃ CsOAc K₂CO₃ K₂HPO₄Bi(OTf)₃ Sc(OAc)₃

Components of the reaction mixture are disposed in a solvent. Anysolvent not inconsistent with the objectives of the present inventioncan be employed. The solvent, for example, can be an aprotic polarsolvent. In some embodiments, the solvent is selected from Table VI.

TABLE VI Solvent of the Reaction Mixture DMSO DMPU DMF DMA NMP CH₃CNIn one embodiment, for example, solvent of the reaction mixture is DMFat a molarity of 0.01 to 0.1M. In other embodiments, suitable solventcan be water or aqueous-based solvent systems. Buffer solutions, forexample, can be employed in reaction mixtures described herein. In someembodiments, pyridinium formate is a suitable buffer solution.

For coupling methods employing photocatalyst, the reaction mixture isirradiated with a radiation source resulting in coupling of the Michaelacceptor with the peptide via a mechanism including decarboxylation ofan amino acid residue. The amino acid residue can be an internal residueor the peptide C-terminal residue. Advantageously, irradiation and thesubsequent reaction can take place at room temperature. Radiation of anywavelength suitable for photocatalyst activation may be employed. Insome embodiments, the radiation source provides radiation in the visibleregion of the electromagnetic spectrum. In some embodiments, theradiation source comprises one or more one compact fluorescent lamps(CFL), light emitting diodes (LED) or combinations thereof. For example,blue LEDs may be used as the radiation source. While visible light isemployed in the examples described herein, radiation of other region(s)of the electromagnetic spectrum are contemplated, including ultravioletand/or infrared radiation. In some embodiments, the reaction is allowedproceed for a time period of 1 to 48 hours.

FIGS. 2-4 illustrate specific examples of peptide functionalizationaccording to methods described herein. As illustrated in FIGS. 2-4, theresulting coupling product is a 1,4-addition adduct comprising thepeptide and a Michael acceptor residue coupled to the decarboxylatedC-terminal residue of the peptide. General protocol for the reactionsdepicted in FIGS. 2-4 is provided in the examples section below.

FIGS. 5A-SE also illustrate examples of C-terminus peptidefunctionalization under various reaction conditions according to someembodiments described herein. General reaction conditions are providedin FIG. 5A wherein a tetramer of X-glycine-phenylalanine-proline isprovided. The N-terminal residue (X) was varied as illustrated in FIGS.5B-SE to determine effect on yield of C-terminal functionalized peptide.Specific reaction conditions were also varied (conditions A-D) asprovided in FIGS. 5B-5E respectively. As detailed in FIGS. 5A-SE,peptide functionalization via decarboxylative pathways occurs in goodyield over a variety of substrates and reaction conditions withtransition metal catalyst and organic catalyst.

FIGS. 6A-6C illustrate various Michael acceptors for peptidefunctionalization at the C-terminus under differing catalyst conditionsaccording to some embodiments described herein. As provided in FIG. 6A,iridium photocatalyst is employed in condition A and riboflavintetrabutyrate photocatalyst is provided in condition B. A variety ofMichael acceptors were compatible with decarboxylative mechanismsdescribed herein resulting in C-terminal functionalization.

In further embodiments, interior residues having carboxyl moieties canundergo functionalization with Michael acceptors via decarboxylativemechanisms described herein. Interior aspartic acid and/or glutamic acidresidues, for example, can participate in peptide functionalizationdescribed herein. Moreover, unnatural amino acids or amino acidderivatives having carboxyl functionality can be located at interiorpositions of the peptide chain. Such amino acids and derivatives mayalso participate in peptide functionalization. FIGS. 7A-7C illustratepeptide functionalization at interior locations via decarboxylativemechanisms described herein. As provided in FIG. 7A, Ubiquitin is addedto a reaction mixture with Michael acceptor and photocatalyst fordecarboxylative functionalization. Shorter peptide sequences or segmentsof Ubiquitin are also shown in FIG. 7 as part of analyticalcharacterization of functionalized peptide. FIGS. 7B and 7C summarizeinterior amino acid functionalization with respect to iridium andriboflavin tetrabutyrate photocatalyst. As illustrated in FIGS. 7B and7C, Ubiquitin was functionalized with Michael acceptor at various acidicresidue interior locations.

II. Decarboxylative Peptide Coupling

In another aspect, methods of peptide coupling are described herein. Amethod of peptide coupling comprises providing a reaction mixtureincluding a first peptide and a second peptide, the second peptidecomprising a Michael acceptor functionalized N-terminal residue andcoupling the functionalized N-terminal residue with the first peptidevia a mechanism including decarboxylation of an amino acid residue ofthe first peptide. In some embodiments, the first peptide C-terminalresidue undergoes decarboxylative coupling with the Michael acceptorfunctionalized N-terminal residue of the second peptide. In otherembodiments, an interior amino acid residue of the first peptideundergoes decarboxylative coupling with the Michael acceptorfunctionalized N-terminal residue of the second peptide.

The first peptide and the second peptide can each have any desirednumber of amino acids not inconsistent with the objectives of thepresent invention. In some embodiments, each of the first and secondpeptides has a number of amino acids selected from Table I herein. Thepeptide can also include unnatural amino acids and/or amino acidderivatives. For example, the peptide can include unnatural amino acidsor derivatives of Table II herein. Further, various Michael acceptorscan be employed to functionalize the N-terminal residue. For example, insome embodiments, crotonic acid or crotonic acid derivative can bereacted with the terminal amine to provide a Michael acceptorfunctionalized N-terminus.

The reaction mixture can also include one or more catalytic species toassist in the decarboxylative coupling of the first and second peptides.Catalytic species, in some embodiments, participate in forming acarboxyl radical on a residue of the first peptide which then rapidlyextrudes CO₂ to produce an amino radical. The amino radical issubsequently operable to undergo conjugate addition with the N-terminalpendant Michael acceptor of the second peptide to forge a new C—C bondresulting in peptide coupling. Catalyst can participate in carboxylradical formation via a single electron transfer (SET) process. Forexample, catalyst can act in an oxidative capacity to produce thecarboxyl radical followed by CO₂ extrusion. Alternatively, catalyst canact in reductive capacity to produce the carboxyl radical followed byCO₂ extrusion. Any catalyst operable to initiate a carboxyl radical ofthe C-terminus residue or an interior acid residue followed by CO₂extrusion is contemplated herein. In some embodiments, catalyst can alsoclose the redox cycle by single electron transfer (SET) to the α-acylradical formed by the conjugate addition. In other embodiments,different catalytic species or co-catalysts are used for carboxylradical formation and acyl radical reduction.

Various transition metal catalysts may be operable to participate in theforegoing decarboxylative mechanisms and associated SET and/or redoxprocesses. Nickel catalyst and/or noble metal catalyst, for example, maybe suitable for use in coupling methods described herein. In someembodiments, catalyst is photoredox catalyst. Any photoredox catalystoperable to participate in in decarboxylative mechanisms describedherein can be used in the reaction mixture. For example, photoredoxcatalyst can include one or more iridium complexes. In some embodiments,heteroleptic iridium and/or ruthenium complexes are selected as thephotocatalyst. Suitable heteroleptic iridium complexes includeIr[dF(CF₃)ppy]₂(dtbbpy)⁺, Ir(dF(CF₃)ppy)₂ (4,4′-dcbpy) andIr(ppy)(dtbbpy)⁺. Homoleptic iridium complexes, such as Ir(dFppy)₃, canalso be used as photocatalyst. Moreover, photoredox catalyst may bepresent in the reaction mixture in an amount selected from Table IVherein.

In further embodiments, one or more electrochemical methods may be usedto initiate carboxyl radical formation and/or acyl radical reduction.For example, one or more electrodes can be positioned in the reactionmixture to initiate decarboxylative mechanisms and associated SET and/orredox processes described herein. Additionally, one or more reducingmetals, such as zinc, may be used to initiate carboxyl radical formationand/or acyl radical reduction.

Moreover, base and solvent components described in Section I above cancomplete the reaction mixture. FIG. 8 illustrates a non-limiting exampleof peptide coupling according to one embodiment of a method describedherein. General protocol for administering the peptide coupling of FIG.8 is provided in the examples section below.

III. Decarboxylative Peptide Intramolecular Cyclicization

In a further aspect, methods of intramolecular peptide cyclization aredescribed herein. For example, a method of intramolecular peptidecyclization comprises providing a reaction mixture comprising a peptideincluding a C-terminal residue and a Michael acceptor functionalizedN-terminal residue and coupling the C-terminal residue with thefunctionalized N-terminal residue via a mechanism includingdecarboxylation of the C-terminal residue. Coupling of thefunctionalized N-terminal residue with the C-terminal residue results incyclization of the peptide.

The peptide can have any desired number of amino acids commensurate withintramolecular cyclization according to mechanistic pathways describedherein. In some embodiments, the peptide has at least three amino acids.In some embodiments, the peptide has a number of amino acids selectedfrom Table I herein. The peptide can also include unnatural amino acidsand/or amino acid derivatives. For example, the peptide can includeunnatural amino acids or derivatives of Table II herein. Further, theMichael acceptor functionalized N-terminal residue can have structure asdescribed in Section II above.

As provided in the specific examples below, peptide substratescontaining oxidation-sensitive functionality, such as thioethers andindoles present in the side chains of Met and Trp, can be readilycyclized under redox conditions described herein. In addition protectedamines, amides, and guanidiniums (Lys, Gln, and Arg) can be incorporatedinto cyclic peptide products. Linear sequences containing thenon-natural amino acids N-methyl alanine and propargyl glycine undergophotoredox macrocyclization with exceptional efficiency. Heteroaromaticside chains are also tolerated, with a substrate containing protectedHis undergoing cyclization in 65% yield. Intriguingly, a substratecontaining a C-terminal Glu residue shows complete selectivity fordecarboxylation at the terminal carboxylic acid over reaction on theside chain. This result can be rationalized by the oxidation potentialdifference between carboxyl functionality adjacent to radicalstabilizing heteroatoms and primary alkyl carboxylic acids. In additionto tolerating a variety of functionalized side chains, methods describedherein are also amenable to substitution at the terminal amino acid andMichael acceptor portions of the precursor linear sequences.Incorporating a radical-stabilizing phenyl group at the α-position ofthe Michael acceptor results in excellent reaction efficiency and goodlevels of diastereoselectivity. The use of substituted amino acidN-methyl leucine at the C-terminus also results in a highly efficientmacrocyclization reaction. Furthermore, bicyclic spiro products can bereadily generated through the use of fully substituted carboxylic acids.

The reaction mixture can include one or more catalytic species to assistin decarboxylative intramolecular cyclization of the peptide. Catalyticspecies, in some embodiments, participate in forming a carboxyl radicalon a residue which then rapidly extrudes CO₂ to produce an aminoradical. The amino radical is subsequently operable to undergo conjugateaddition with the N-terminal pendant Michael acceptor to forge a new C—Cbond resulting in an α-acyl radical and intramolecular peptidecyclization. Catalyst can participate in carboxyl radical formation viaa single electron transfer (SET) process. For example, catalyst can actin an oxidative capacity to produce the carboxyl radical followed by CO₂extrusion. Alternatively, catalyst can act in reductive capacity toproduce the carboxyl radical followed by CO₂ extrusion. Any catalystoperable to initiate a carboxyl radical of the C-terminus residuefollowed by CO₂ extrusion is contemplated herein. In some embodiments,catalytic species initiating carboxyl radical formation can also closethe redox cycle by single electron transfer (SET) to the α-acyl radicalformed by the conjugate addition. In other embodiments, differentcatalytic species or co-catalysts are used for carboxyl radicalformation and acyl radical reduction.

Various transition metal catalysts may be operable to participate in theforegoing decarboxylative mechanisms and associated SET and/or redoxprocesses. Nickel catalyst and/or noble metal catalyst, for example, maybe suitable for use in coupling methods described herein. In someembodiments, catalyst is photoredox catalyst. Any photoredox catalystoperable to participate in in decarboxylative mechanisms describedherein can be used in the reaction mixture. For example, photoredoxcatalyst can include one or more iridium and/or ruthenium complexes. Insome embodiments, heteroleptic iridium complexes are selected as thephotocatalyst. Suitable heteroleptic iridium complexes includeIr[dF(CF₃)ppy]₂(dtbbpy)⁺, Ir(dF(CF₃)ppy)₂ (4,4′-dcbpy) andIr(ppy)₂(dtbbpy)⁺. Homoleptic iridium complexes, such as Ir(dFppy)₃, canalso be used as photocatalyst. Moreover, photoredox catalyst may bepresent in the reaction mixture in an amount selected from Table IVherein. In some embodiments for example, photoredox catalyst is presentin the reaction mixture in an amount of 5-15 mol % or 8-12 mol %.

In further embodiments, one or more electrochemical methods may be usedto initiate carboxyl radical formation and/or acyl radical reduction.For example, one or more electrodes can be positioned in the reactionmixture to initiate decarboxylative mechanisms and associated SET and/orredox processes described herein. Additionally, one or more reducingmetals, such as zinc, may be used to initiate carboxyl radical formationand/or acyl radical reduction.

The reaction mixture can further comprise co-catalyst operable toparticipate in hydrogen atom transfer (HAT) to carbon centered radicals,such as those encountered in decarboxylative intramolecular peptidecyclization pathways described herein. Suitable co-catalyst can includevarious aryl thiol compounds.

Base and solvent components described in Section I above can completethe reaction mixture for of peptide intramolecular cyclization viadecarboxylation.

FIG. 9 illustrates a mechanistic pathway of peptide intramolecularcyclization via decarboxylation according to one example of a methoddescribed herein. Under irradiation by visible light, photoredoxcatalyst Ir[dF(CF₃)ppy]₂(dtbbpy)⁺ 1 absorbs a photon and accessesexcited state *Ir[dF(CF₃)ppy]₂(dtbbpy)⁺ 2, a strong oxidant (E_(1/2)^(red) [*Ir^(III)/Ir^(II)]=+1.21 V vs SCE in MeCN). SET oxidation of thecarboxylate salt of 3, generated in situ by action of a base,subsequently occurs. The resulting carboxyl radical then rapidlyextrudes CO₂ to produce α-amino radical 4 and reduced photocatalystIr[dF(CF₃)ppy]₂(dtbbpy) 5. Entropically uphill organization ofintermediate 4 into a product-like reactive conformation then occurs.Intramolecular conjugate addition of nucleophilic α-amino radical 4 withthe pendant Michael acceptor constructs the desired C—C bond andprovides α-acyl radical 6. Closure of the photoredox catalytic cycleoccurs via SET reduction of intermediate 6. Finally, protonation of theresulting enolate furnishes desired cyclic peptide product 7.

FIG. 10 illustrates a mechanistic pathway wherein aryl thiol co-catalystis employed for HAT to the acyl radical 6. Subsequent to HAT, theresulting thiyl radical can be reduced by Ir(II) to close thephotocatalytic cycle. FIG. 11 illustrates a non-limiting example ofpeptide intramolecular cyclization according to one embodiment of amethod described herein.

In some embodiments, peptide intramolecular cyclization does not occurbetween the Michael acceptor functionalized N-terminal residue andC-terminus residue. For example, the functionalized N-terminal residuemay react with an interior residue having side chain carboxylfunctionality. In such embodiments, the C-terminus residue can beinactivated with a protecting group. Coupling the functionalizedN-terminal residue to an interior amino acid via a decarboxylativepathway can enable the production of a variety of cyclized peptidestructures. For example, the size of the peptide cyclic structure can bevaried according to the position of the interior residue participatingin the decarboxylative pathway. In some embodiments, reaction of thefunctionalized N-terminal residue with an interior residue is precludedby protecting interior residues having acid functionalities.

IV. Decarboxylative Conjugate Addition

In an additional aspect, general methods of conjugate addition aredescribed herein. A method of conjugate addition comprises providing areaction mixture including a Michael acceptor and a substrate having acarboxyl group and coupling the Michael acceptor and substrate via amechanism including decarboxylation of the substrate.

Any substrate including a carboxyl group operable to undergodecarboxylative mechanistic pathways described herein can be employed inthe reaction mixture. In some embodiments, a substrate of the reactionmixture is an aliphatic carboxylic acid. In being an aliphatic acid, thecarboxyl functional group is not directly bonded to an aromatic ring,such as a phenyl ring. Aliphatic carboxylic acid, in some embodiments,is of the formula R³—CO₂H. R³ can be a saturated hydrocarbon or ahydrocarbon having one or more points of unsaturation. Further,saturated or unsaturated hydrocarbons can incorporate or be substitutedwith one or more heteroatoms including nitrogen, oxygen and/or sulfur.Therefore, R³ can be selected from the group consisting of -alkyl,-cycloalkyl, -heteroalkyl, -heterocycloalkyl, -alkenyl, -cycloalkenyl,-heteroalkenyl, -heterocycloalkenyl, -alkynyl, -alkyl-aryl,-alkyl-hetroaryl, -alkyl-alkoxy, -alkenyl-aryl, -alkenyl-heteroaryl,-cycloalky-aryl, -cycloakyl-heteroaryl, -cycloalkenyl-aryl,-heterocycloalkenyl-aryl, and -alkenyl-alkoxy. FIG. 12 illustratesvarious carboxylic acid substrates according to some embodimentsdescribed herein. Additionally, carboxylic acid substrate can beselected from the amino acids provided in Table I above.

The reaction mixture can also include one or more catalytic species toassist in the decarboxylative coupling of the Michael acceptor andsubstrate. Catalytic species, in some embodiments, participate informing a carboxyl radical which then rapidly extrudes CO₂ to produce analkyl radical. The alkyl radical is subsequently operable to undergoconjugate addition with the Michael acceptor to forge a new C—C bondwith concomitant formation of an α-acyl radical. The α-acyl radical issubsequently reduced by the catalyst. Catalyst can participate incarboxyl radical formation via a single electron transfer (SET) process.For example, catalyst can act in an oxidative capacity to produce thecarboxyl radical followed by CO₂ extrusion. Alternatively, catalyst canact in reductive capacity to produce the carboxyl radical followed byCO₂ extrusion. Any catalyst operable to initiate carboxyl radicalformation followed by CO₂ extrusion is contemplated herein. In someembodiments, catalytic species initiating carboxyl radical formation canalso close the redox cycle by single electron transfer (SET) to theα-acyl radical formed by the conjugate addition. In other embodiments,different catalytic species or co-catalysts are used for carboxylradical formation and acyl radical reduction.

Various transition metal catalysts may be operable to participate in theforegoing decarboxylative mechanisms and associated SET and/or redoxprocesses. Nickel catalyst and/or noble metal catalyst, for example, maybe suitable for use in coupling methods described herein. In someembodiments, catalyst is photoredox catalyst. Any photoredox catalystoperable to participate in in decarboxylative mechanisms describedherein can be used in the reaction mixture. For example, photoredoxcatalyst can include one or more iridium and/or ruthenium complexes. Insome embodiments, heteroleptic iridium complexes are selected as thephotocatalyst. Suitable heteroleptic iridium complexes includeIr[dF(CF₃)ppy]₂(dtbbpy)⁺, Ir(dF(CF₃)ppy)₂ (4,4′-dcbpy) andIr(ppy)₂(dtbbpy)⁺. Homoleptic iridium complexes, such as Ir(dFppy)₃, canalso be used as photocatalyst. Moreover, photoredox catalyst may bepresent in the reaction mixture in an amount selected from Table IVherein.

In further embodiments, one or more electrochemical methods may be usedto initiate carboxyl radical formation and/or acyl radical reduction.For example, one or more electrodes can be positioned in the reactionmixture to initiate decarboxylative mechanisms and associated SET and/orredox processes described herein. Additionally, one or more reducingmetals, such as zinc, may be used to initiate carboxyl radical formationand/or acyl radical reduction. Base and solvent components described inSection 1 above complete the reaction mixture.

While not wishing to be bound by any theory FIG. 13 illustrates amechanistic pathway of conjugate addition via decarboxylation accordingto one example of a method described herein. Iridium photoredoxcatalyst, such as Ir[dF(CF₃)ppy]₂(dtbbpy)⁺ 1 can readily accept photonsfrom a visible light source to generate the strongly oxidizing excitedstate *Ir[dF(CF₃)ppy]₂(dtbbpy)⁺ 2. The carboxylic acid 3 undergoesbase-promoted deprotonation and subsequent single electron transfer(SET) oxidation of the resulting carboxylate functionality by thevisible-light-excited photocatalyst *Ir[dF(CF₃)ppy]₂(dtbbpy)⁺ 2, therebygenerating the reduced Ir[dF(CF₃)ppy]₂(dtbbpy) 6 and the carboxylradical species which immediately extrudes CO₂ to give the SOMO species4. The alkyl radical 4 undergoes conjugate addition with the electrondeficient olefin 5 to forge a new C—C bond with concomitant formation ofthe alkyl radical 7. Facile SET reduction of the α-acyl radical 7 by thestrongly reducing Ir[dF(CF)ppy]₂(dtbbpy) 6 provides the 1,4-conjugateaddition product while regenerating the Ir[dF(CF₃)ppy]₂(dtbbpy)⁺ 1photocatalyst.

Examples of conjugate addition, peptide functionalization, peptidecoupling and peptide intramolecular cyclization are provided in thefollowing Examples section.

V. Examples

Materials and Methods

The following Examples were conducted with the materials and methodsdescribed herein. Commercial reagents were purchased from Sigma Aldrichand purified prior to use following the guidelines of Perrin andArmarego, Purification of Laboratory Chemicals, Pergamon, Oxford, ed. 31988) (hereinafter “Perrin”). All solvents were purified by passagethrough columns of activated alumina. Organic solutions wereconcentrated under reduced pressure on a Büchi rotary evaporator usingan acetone-dry ice bath for volatile compounds. Chromatographicpurification of products was accomplished by flash chromatography onsilica gel (Fluka, 230-400 mesh). Thin layer chromatography (TLC) wasperformed on Analtech Uniplate 250 m silica gel plates. Visualization ofthe developed chromatogram was performed by fluorescence quenching,p-anisaldehyde, potassium permanganate, or ceric ammonium molybdatestain. ¹H and ¹³C NMR spectra were recorded on a Bruker 500 (500 and 125MHz) instrument, and are internally referenced to residual protiosolvent signals (note: CDCl₃ referenced at 7.26 and 77.0 ppmrespectively). Data for ¹H NMR are reported as follows: chemical shift(δ ppm), integration, multiplicity (s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet), coupling constant (Hz) and assignment. Data for¹³ _(C) NMR are reported in terms of chemical shift and no specialnomenclature is used for equivalent carbons. High resolution massspectra were obtained at Princeton University mass spectrometryfacilities. All amino acids were used from commercial suppliers. Allaryl and heteroaryl halides were used from commercial suppliers orprepared using standard literature procedures.

General Procedure for Decarboxylative Peptide Functionalization (FIGS.3-4)

To an 8 m vial equipped with a magnetic stir bar was addedCbz-βAla-Ala-Phe-Gly-Ala-Phe-Gly-Val-OH (SEQ ID NO: 1) (0.10 mmol, 1.0equiv.), diethyl 2-ethylidenemalonate (0.10 mmol, 1.0 equiv.), cesiumacetate (0.12 mmol, 1.2 equiv.), Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (1.0 μmol,0.01 equiv.), and 1.0 mL of DMF. The vial was sealed with a Teflon capand sparged with nitrogen gas for 15 min (solution changes from yellowto a pale green). Then, the vial was sealed with parafilm and placedinside a fan-cooled reflective chamber. Finally, the vial was exposed toone 34 W blue LED under magnetic stirring for 48 hr. Peptides over 4residues in length can be precipitated out by addition of an excess ofcold diethyl ether in preparation for purification by reverse-phaseHPLC. For shorter peptide sequences, the reaction mixture was dilutedwith a saturated aqueous NaHCO₃ solution and extracted with ethylacetate (3×50 mL). The combined organic extracts were washed with waterand brine, dried over anhydrous MgSO₄, and concentrated in vacuo.Purification of the crude product by flash chromatography on silica gelafforded the desired product.

General Procedure for Decarboxylative Peptide Coupling (FIG. 8)

To an 8 mL vial equipped with a magnetic stir bar was addedCbz-Phe-Leu-Gly-Pro-OH (SEQ ID NO: 2)(0.10 mmol, 1.0 equiv.),Crotonyl-Phe-Ala-Pro-Gly-OMe (SEQ ID NO: 3) (0.10 mmol, 1.0 equiv.),dibasic potassium phosphate (0.12 mmol, 1.2 equiv.),Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (1.0 μmol, 0.01 equiv.), and 1.0 mL of DMF.The vial was sealed with a Teflon cap and sparged with nitrogen gas for15 min (solution changes from yellow to a pale green). Then, the vialwas sealed with parafilm and placed inside a fan-cooled reflectivechamber. Finally, the vial was exposed to one 26 W CFL bulb undermagnetic stirring for 48 hr. The crude material can be precipitated outby addition of an excess of cold diethyl ether in preparation forpurification by reverse-phase HPLC.

General Procedure for Decarboxylative Peptide Intramolecular Cyclization

Commercial reagents were purified prior to use following the guidelinesof Perrin and Armarego. (Perrin, D. D.; Armarego, W. L. F. Purificationof Laboratory Chemicals, 3rd ed. Pergamon Press: Oxford, 1988).Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ was prepared according to the literatureprocedure. (Lowry, M. S.; Goldsmith, J. L; Slinker, J. D.; Rohl, R.;Pascal, Jr., R. A.; Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005,17, 5712). 2,4,6-Triisopropylbenzenethiol was prepared according toliterature procedure and purified by distillation prior to use. (Renard,M.; Ghosez, L. A. Tetrahedron 2001, 57, 2597). All solvents werepurified according to the method of Grubbs. (Pangborn, A. B.; Giardello,M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and ConvenientProcedure for Solvent Purification. Organometallics 19%, 15, 1518).Organic solutions were concentrated under reduced pressure on a Büchirotary evaporator using a water bath. Solid phase peptide synthesis wasperformed on 2-chlorotrityl chloride resin (100-200 mesh, 1.2 meq/g,crosslinked polystyrene) manually or on a Prelude automated peptidesynthesizer. 2-chlorotrityl chloride resin,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N,N-diisopropylethylamine (DIPEA), and Fmoc-amino acids werepurchased from Chem impex Int'l Inc. and used as received.1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was purchased from OakwoodChemical and used as received. ¹H NMR spectra were recorded on a BrukerUltraShield Plus 500 MHz unless otherwise noted and are internallyreferenced to residual protio CD₃OD signals (3.31 ppm). Data for ¹H NMRare reported as follows: chemical shift (δ ppm), multiplicity(s=singlet, d=doublet, t=triplet, q quartet, m=multiplet, dd=doublet ofdoublets, dt doublet of triplets, br=broad), coupling constant (Hz), andintegration. (CD₃)₂SO was added for solubility when necessary. ³C NMRspectra were recorded on a Bruker UltraShield Plus 500 MHz and data arereported in terms of chemical shift relative to CD₃OD (49.2 ppm). HighResolution Mass Spectra were obtained from the Princeton University MassSpectral Facility.

Synthesis of Linear Peptide Sequences

General Solid Phase Loading Procedure:

into a 12 mL filtration tube with luer adapter was added 2-chlorotritylchloride resin (500 mg, 600 μmol) followed by a solution of the Fmocamino acid (1.8 mmol, 3 equiv.) and DIPEA (0.627 mL, 3.6 mmol, 6 equiv.)in CH₂Cl₂ (8 mL). The tube was capped and shaken for 15 minutes and thenan additional 2 equiv. of DIPEA added. After a further hour of shaking,2 equiv. DIPEA and 1 ml. MeOH was added and the mixture agitated for 20minutes. The tube was then drained, rinsed with CH₂Cl₂ (3×8 mL) anddried. The amino acid loading of the resin was then measured by Fmocdetermination. (Boll, E.; Drobecq, H.; Ollivier, N.; Blanpain, A.;Raibaut, L; Desmet, R.; Vicogne, J.; Melnyk, O. Nature Protocols 2015,10, 269)

General Solid Phase Synthesis Procedure:

The resin was treated with 20% piperidine/DMF (6 mL) for 5 minutesfollowed by thorough washing with DMF (6×6 mL). Deprotection wasperformed twice.

A solution of Fmoc-protected amino acid (1.8 mmol, 3 equiv.) and HBTU(0.68 g, 1.8 mmol, 3 equiv.) in DMF (6 mL) followed by DIPEA (0.627 mL,3.6 mmol, 6 equiv.) was added to the resin and the mixture shaken for 2hours. The resin was then drained and rinsed with DMF (6×6 mL). Ifnecessary, the coupling procedure was repeated until completion.

General Acryloyl Capping Procedure;

A solution of pentafluorophenyl acrylate (0.43 g, 1.8 mmol, 3 equiv.,prepared according to literature procedure) and DIPEA (0.627 mL, 3.6mmol, 6 equiv.) in DMF (6 mL) was added to the resin and the mixtureshaken for 4 hours. The resin was drained and rinsed with DMF (6×6 mL).The procedure was repeated twice.

General Resin Cleavage Procedure:

After completion of synthesis, resin was thoroughly rinsed with DMF (6×6mL) then CH₂Cl₂ (6×6 mL). The resin was then treated with 4:1CH₂Cl₂:HFIP twice for 1 hour each. The combined CH₂Cl₂:HFIP solutionswere concentrated under reduced pressure. Cold Et₂O was added to theremaining solid, which was then centrifuged and decanted; this procedurewas repeated twice. The remaining solid was dried under a stream of N₂and then under reduced pressure to yield the desired crude peptide. Ifnecessary, preparative HPLC purification was carried out.

General Decarboxylative Macrocyclization Procedure

General Procedure for the Decarboxylative Macrocyclization of N-AcryloylPeptides:

To a dry 8 ml vial equipped with a stir bar was addedIr[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1.3 mg, 1.2 μmol, 0.12 equiv.), peptide(10.0 μmol, 1.0 equiv.), K₂HPO₄ (3.5 mg, 20.0 μmol, 2.0 equiv.), water(0.36 μL, 20.0 μmol, 2.0 equiv.), and DMF (4 mL). The vial was cappedand the reaction mixture was degassed by sparging with N₂ while stirringat 800 RPM for 20 min before sealing the vial with Parafilm. Thereaction was stirred at 800 RPM and irradiated with a 34 W blue LED lampuntil complete consumption of the starting material, typically within 6hours. The reaction was centrifuged and subjected to RP-HPLC analysisfor yield determination.

The crude materials were purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 30×150 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid;Gradient: 10-70% B over 20 minutes, then a 2-minute hold at 100% B;Flow: 40 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation.

Two analytical LC/MS injections were used to determine the final purity.Injection I conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,1.7-μm particles; Mobile Phase A: 5:95 acetonitrile; water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection:UV at 220 nm. Injection 2 conditions: Column: Waters Acquity UPLC BEHC18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B;Flow: 1.0 mL/min; Detection: UV at 220

cyclo-[Aba-Phe-Met-Leu-Glu(OtBu)] (SEQ ID NO: 4)

Prepared following the general procedure outlined above usingacryloyl-Phe-Met-Leu-Glu(tBu)-Gly (SEQ ID NO: 5)(7.1 mg, 10 μmol, 1.0equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PFs (1.3 mg, 1.2 μmol, 0.12 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), 2, 4, 6-triisopropylbenzenethiol(0.24 mg, 1 μmol, 0.1 equiv.), and DMF (4.0 mL). After 10 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 40%. ¹H NMR (500 MHz, CD₃OD)7.35-7.22 (m, 5H), 4.41 (t, J=7.8 Hz, 1H), 4.26-4.22 (m, 1H), 3.96 (dd,J=11.2, 4.1 Hz, 1H), 3.87 (dd, J=9.5, 4.0 Hz, 1H), 3.15-3.03 (m, 2H),3.03-2.94 (m, 1H), 2.48 (ddd, J=15.7, 8.9, 5.3 Hz, 1H), 2.37-2.21 (m,1H), 2.21-2.04 (m, 41), 2.02 (s, 3H), 2.01-1.96 (m, 2H), 1.86-1.79 (m,1H), 1.74 (ddd, J=13.8, 10.0, 4.1 Hz, 1H), 1.68-1.60 (m, 1H), 1.46 (s,9H), 0.95 (dd, J=13.7, 6.5 Hz, 6H); HRMS (ESI-TOF) m/z calcd. forC₃₃H₅₂NsO₇S ([M+H]⁺) 662.35820. found 662.35806.

cyclo-[Aba-Val-Thr(tBu)-Phe-Trp(Boc) (SEQ 1) NO: 6)

Prepared following the general procedure outlined above usingacryloyl-Val-Thr(Bu)-Phe-Trp(Boc)-Gly (SEQ ID NO: 7) (8.2 mg, 10 μmol,1.0 equiv.), Ir(dF(CF)ppy]₂(dtbbpy)PF₆ (1.3 mg, 1.2 μmol, 0.12 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMF (4.0 mL.). After 6 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 56%. ¹H NMR (500 MHz, CD₃OD) δ 8.13(d. J=8.4 Hz, 1H), 7.64 (d, J=7.8 Hz, H), 7.38 (s, 1H), 7.33 (t, J=7.7Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.16-7.03 (m, 5H), 4.27 (dd, J=10.8,4.7 Hz, 1H), 4.18 (q, J 4.9, 4.3 Hz, 2H), 4.14 (d, =4.5 Hz, 1H),4.09-4.01 (m, 1H), 3.49-3.37 (m, 4H), 3.07-2.93 (m, 2H), 2.45 (ddd,J=13.1, 8.3, 4.2 Hz, 1H), 2.34-2.18 (m, 2H), 2.05-1.86 (m, 2H), 1.60 (s,9H), 1.18 (s, 9H), 1.07 (d, J=6.5 Hz, 3H), 0.98 (dd, J=13.5, 6.8 Hz,6H); HRMS (ESI-TOF) m/z calcd. for C₄₂H₅₉N₆O₈ ([M+H]⁺) 775.43889, found775.43881.

cyclo-[Aha-Phe-Arg(Bo)₂-Ser(tBu)-Ala] (SEQ ID NO: 8)

Prepared following the general procedure outlined above usingacryloyl-Phe-Arg(Boc)₂-Ala-Ser(tBu)-Gly (SEQ ID NO: 9)(8.5 mg, 10 μmol,1.0 equiv.), Ir[dF(CF)ppy]2(dtbbpy)PF₆ (2.2 mg, 2.0 μmol, 0.20 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), 2, 4, 6-triisopropylbenzenethiol(0.24 mg, 1 μmol, 0.1 equiv.), and DMF (4.0 mL). After 12 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 59%. ¹H NMR (500 MHz, CD₃OD) δ7.33-7.19 (m, 5H), 4.50 (t, J=7.7 Hz, 1), 4.23 (dd, J=7.1, 3.8 Hz, 1H),4.06 (q, J=7.2 Hz, 1H), 3.98-3.86 (m, 2H), 3.76 (dd. J=9.5, 3.8 Hz, 1),3.40-3.21 (m, 2H), 3.13-3.07 (m, 21), 2.97 (dd, J=13.7, 8.0 Hz, 1H),2.29 (ddd. J=13.6, 8.4, 4.6 Hz, 1H), 2.21 (ddd, J=14.6, 7.4, 4.71 Hz,1H), 1.94-1.86 (m, 41), 1.78 (dtd, J=14.0, 9.8, 4.9 Hz, 1H), 1.54 (s,9H), 1.46 (s, 91), 1.44-1.38 (m, 1H), 1.35-1.27 (m, 1H), 1.23 (s, 9H),1.20-1.16 (m, 2H). HRMS (ESI-TOF) m/z calcd. for C₃₉H₆₃N₈O₁₀ ([M+H]⁺)803.46617, found 803.46697.

cyclo-[Aba-Phe-Gln(Trt)-Leu-Lys(Boc)] (SEQ ID NO: 10)

Prepared following the general procedure outlined above usingacryloyl-Phe-Gln(Trt)-Leu-Lys(Boc)-Gly (SEQ ID NO: 11) (9.9 mg, 10 μmol,1.0 equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1.3 mg, 1.2 mol, 0.12 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMF (4.0 mL). After 6 h. thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 94%, 1H NMR (500 MHz, CD₃OD) δ7.33-7.16 (m, 20H), 4.38 (dd, J=9.1, 6.3 Hz, 1H), 4.15-4.05 (m, 1H),3.95 (dd, J=11.0, 4.1 Hz, 1H), 3.70 (d, J=8.9 Hz, 1H), 3.20-2.89 (m,6H), 2.31-2.19 (m, 4H), 2.15-2.02 (m, 2H), 2.02-1.87 (m, 3H), 1.85-1.78(m, 1H), 1.78-1.63 (m, 2H), 1.50-1.42 (m, 12H), 1.34-1.29 (m, 1H), 0.95(dd, J=13.2, 6.3 Hz, 6H); HRMS (ESI-TOF) m/z: calcd. for C₅₄H₇₀N₇O₈([M+H]⁺) 944.52084, found 944.52716.

cyclo-[Aba-Phe-(Me)Ala-Tyr(tBu)-Val] (SEQ ID NO: 12)

Prepared following the general procedure outlined above usingacryloyl-Phe-(Me)Ala-Tyr(tBu)-Val-Gly (SEQ ID NO: 13) (6.8 mg, 10 μmol,1.0 equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (0.9 mg, 0.8 μmol, 0.08 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMF (2.0 mL). After 10 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 66%. ¹H NMR (500 MHz, CD₃OD) NMRspectrum complicated due to the presence of rotamers. S 7.34-7.21 (m,5H), 7.13 (dd, J=18.4, 8.1 Hz, 2H), 6.92 (dd, J=20.1, 8.1 Hz, 2H), 4.37(t, J=11.9 Hz, 1H), 4.28 (q, J=6.9 Hz, 1H), 4.14 (dt, J=10.2, 5.5 Hz,2H), 3.29-3.19 (m, 2H), 3.09 (dt, J=13.1, 6.01 Hz, 1H), 3.05-2.84 (m,2H), 2.63 (s, 3H), 2.58-2.46 (m, 1H), 2.43-2.27 (m, 3H), 2.23-2.13 (m,1H), 1.95-1.86 (m. I H), 1.85-1.73 (m, 1H), 1.30 (s, 9H), 0.96 (d, J=6.8Hz, 3H), 0.75 (d, J 6.9 Hz, 3H), 0.34 (d, J=6.7 Hz, 3H); HRMS (ESI-TOF)m/z calcd. for C₃₅H₅₀N₅O₆ ([M+H]⁺) 636.37556, found 636.37528.

cyclo-[Aba-Phe-Pra-Ala-Lys(Boc)] (SEQ 1: NO: 14)

Prepared following the general procedure outlined above usingacryloyl-Phe-Pra-Ala-Lys(Boc)-Gly (SEQ ID NO: 15)(6.7 mg, 10 μmol, 1.0equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (0.9 mg, 0.8 μmol, 0.08 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMF (2.0 mL). After 10 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 82%. Rotameric ¹H NMR spectrum. ¹HNMR (500 MHz, CD₃OD) δ 7.39-7.23 (m, 5H), 4.49-4.35 (m, 1.2H), 4.31-4.24(m, 0.8H), 4.01-3.96 (m, 2H), 3.36-3.27 (m, 2H), 3.15-3.05 (m, 3H), 3.03(s, 1H), 3.01-2.87 (m, 2H), 2.88-2.77 (m, 1H), 2.43 (t, J=2.6 Hz, 1H),2.38-2.28 (m, 1H), 2.27-2.21 (m, 1H), 2.17-2.00 (m, 1H), 1.95 (m, 1H),1.88-1.83 (m, 1H), 1.82-1.65 (m, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.56-1.49(m, 2H), 1.46 (s, 9H), 1.36 (m, 1H); δ HRMS (ESI-TOF) m/z calcd. forC₃₂H₄₇N₆O₇ ([M+H]⁺) 627.35007, found 627.34889.

cyclo-[Aba-Phe-Leu-Ala-His(Trt)] (SEQ ID NO: 16)

Prepared following the general procedure outlined above usingacryloyl-Phe-Leu-Ala-His(Trt)-Gly (SEQ ID NO: 17) (0.84 mg, 1 μmol, 1.0equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (0.13 mg, 0.12 μmol, 0.12 equiv.),K₂HPO₄ (0.35 mg, 2 μmol, 2.0 equiv.), and DMF (1.0 mL). After 20 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions; Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O 0.1% formic acid over 12 minutes.Reaction yield was determined to be 65%. ¹H NMR (500 MHz, CD₃OD) δ7.49-7.20 (m, 2211), 4.48 (dd, J=10.6, 3.8 Hz, 1H), 4.38 (dd, J=9.0, 6.5Hz, 1H), 3.96 (q, J=7.1, 1H), 3.75 (dd, J=10.4, 4.5 Hz, 1H), 3.18-3.09(m, 2H), 3.07-3.01 (m, 1H), 2.95 (dd, J=13.9, 8.9 Hz, 1H), 2.38-2.29 (m,1H), 2.28-2.21 (m, 1H), 2.10-1.97 (m, 1H), 1.77 (br s, 1H), 1.65-1.57(m, 1H), 1.56-1.49 (m, 1H), 1.40 (d, J=7.1 Hz, 3H), 1.36-1.21 (m, 2H),0.99-0.87 (m, 1H), 0.84 (dd, J=13.1, 6.5 Hz, 6H); HRMS (ESI-TOF) m/zcalcd. for C₄₇H₅₄N₇O₅ ([M+H]) 796.41809, found 796.41739.

cyclo-[Ahda-Phe-Leu-Ala-Phe] (SEQ ID NO: 18)

Prepared following the general procedure outlined above usingacryloyl-Phe-Leu-Ala-Phe-Glu.TFA (SEQ ID NO: 19) (7.4 mg, 10 μmol, 1.0equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1.3 mg, 1.2 μmol, 0.12 equiv.),K₂HPO₄ (10.5 mg, 60 mol, 6.0 equiv.), and DMF (4.0 mL). After 12 h. thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 38%. ¹H NMR (500 MHz, CD₃OD) δ7.35-7.18 (m, 10H), 4.58 (td, J=8.1, 2.0 Hz, 1H), 4.08 (dt, J=9.8, 6.4Hz, 1H), 3.92-3.80 (m, 2H), 3.71 (br s, 1H), 3.40-3.36 (m, 1H), 3.09(dt, J:=13.8, 8.0 Hz, 1H), 2.97 (dd, J=13.7, 8.0 Hz, 1H), 2.50 (ddd,J=21.9, 9.9, 4.9 Hz, 1H), 2.42-2.27 (m, 2H), 2.22 (dt, J=15.4, 4.9 Hz,1H), 2.13-1.95 (m, 3H), 1.84-1.72 (m, 2H), 1.44 (ddt, J=13.7, 9.7, 5.2Hz, 1H), 1.32 (d, J=7.1 Hz, 3H), 1.27 (br s, 1H), 0.89 (dd, J=30.5, 6.5Hz, 6H); HRMS (ESI-TOF) m/z calcd. for C₃₄H₄₆N₅O₇ ([M+H]⁺) 636.33918,found 636.33862.

cyclo-[Aba-Phe-Leu-Ala-Phe](SEQ ID NO: 20)

Prepared following the general procedure outlined above usingacryloyl-Phe-Leu-Ala-Phe-Gly (SEQ ID NO: 21) (6.1 mg, 10 μmol, 1.0equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1.3 mg, 1.2 mol, 0.12 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMF (4.0 mL). After 6 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis.

Conditions: Vydac 218TP C18 5μ, length 150 mm, ID 4.6 mm, 40-80%MeCN/H₂O+0.1% formic acid over 12 minutes. Reaction yield was determinedto be 93%. ¹H NMR (500 MHz, CD₃OD) δ 7.34-7.18 (m, 10H), 4.49 (t, J=7.8Hz, 1H), 4.23 (dd, J=11.3, 4.4 Hz, 1H), 3.96 (q, J=7.0 Hz, 1H), 3.80(dd, J=11.0, 4.0 Hz, 1H), 3.39-3.22 (m, 3H), 3.21-3.13 (m, 2H), 3.09(dd, J=13.8, 8.1 Hz, 1H), 3.00 (dd, J=13.7, 7.7 Hz, 1H), 2.29 (dd,J=8.3, 4.8 Hz, 2H), 1.93 (q, J=6.5 Hz, 2H), 1.80 (ddd. J=14.6, 11.1, 4.4Hz, 1H), 1.52 (ddd, J=13.8, 9.9, 4.2 Hz, 1H), 1.28 (d, J=7.3 Hz, 3H),1.21-1.09 (m, 1H), 0.87 (d, J=6.6 Hz, 3H), 0.81 (d, J=6.5 Hz, 3H)¹³C NMR(126 MHz, CD₃OD) δ 175.90, 174.94, 174.76, 174.41, 173.99, 139.92,138.14, 130.40, 130.37, 129.83, 129.63, 128.13, 127.77, 58.24, 57.07,54.48, 52.27, 40.21, 39.74, 38.55, 36.99, 33.70, 25.67, 24.25, 24.19,21.38, 16.65; HRMS (ESI-TOF) m/z calcd. for C₃₁H₄₂N₅O₅ ([M+H]⁺)564.31805, found 564.31752.

cyclo-[Aba-Phe-Leu-Ai-Phe(4-Br)] (SEQ ID NO: 22)

Prepared following the general procedure outlined above usingacryloy-Phe-Leu-Ala-Phe(4-Br)-Gly (SEQ ID NO: 23) (0.42 mg, 1 μmol, 1.0equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (0.13 mg, 0.12 μmol, 0.12 equiv.),K₂HPO₄ (0.35 mg, 2 μmol, 2.0 equiv.), 2, 4, 6-triisopropylbenzenethiol(0.024 mg, 0.1 μmol, 0.1 equiv.), and DMF (0.4 mL). After 7 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 48%. ¹H NMR (500 MHz, CD₃OD) δ7.49-7.45 (m, 2H), 7.33-7.27 (m, 4H), 723-7.19 (m, 3H), 4.49 (t, J=8.0Hz, 1H), 4.24 (ddd, J=11.5, 7.4, 4.2 Hz, 1H), 3.97 (td, J=8.2, 7.4, 5.5Hz, 1H), 3.77 (ddd, J=11.1, 7.0, 4.0 Hz, 1H), 3.38 (dt, J=12.9, 6.2 Hz,1H), 3.33-3.21 (m, 2H), 3.20-3.11 (m, 1H), 3.08-2.94 (m, 2H), 2.37-2.23(m, 2H), 2.00-1.87 (m, 2H), 1.79 (ddd, J=13.4, 11.1, 4.1 Hz, 1H), 1.49(ddd, J=13.8, 10.1, 4.1 Hz, 1H), 1.27 (d, J=7.2 Hz, 3H), 1.09-0.90 (m,2H), 0.88 (d, J=6.5 Hz, 3H), 0.80 (d, J=6.4 Hz, 3H); HRMS (ESI-TOF) m/zcalcd. for C₃₁H₄₁BrN₅O₅ ([M+H]⁺) 642.22856, found 642.22785.

cyclo-[Aba(2-Ph)-Phe-Le-Ala-Phe] (SEQ ID NO: 24)

Prepared following the general procedure outlined above usingα-phenylacryloyl-Phe-Leu-Ala-Phe-Gly (SEQ ID NO: 25)(6.8 mg, 10 μmol,1.0 equiv.), Ir[d(CF₃)ppy]₂(dtbbpy)PF₆ (1.3 mg, 1.2 μmol, 0.12 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMF (4.0 mL). After 6 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 95%, 10:1 dr. ¹H NMR (500 MHz,CD₃OD) δ 7.40-7.12 (m, 15H), 4.58 (t, J=7.9 Hz, 1H), 4.27 (dd, J=8.9,6.7 Hz, 1H), 3.97 (q, J=7.2 Hz, 1H), 3.78 (dd, J=11.1, 4.1 Hz, 1H), 3.52(dd, J=10.3, 4.7 Hz, 1H), 3.39-3.24 (m, 41), 3.07-2.99 (m, 1H), 2.89(dd, J=13.8, 7.9 Hz, 1H), 2.28-2.21 (m, 1H), 2.12-2.06 (m, 1H), 1.84(ddd, J=13.2, 11.2, 4.3 Hz, 1H), 1.49 (ddd, J=13.7, 10.1, 4.2 Hz, 1H),1.28 (d, J=7.31 Hz, 3H), 1.2-1.11 (m, 1H), 0.88 (d, J=6.5 Hz, 3H), 0.82(d, J=6.5 Hz, 3H); HRMS (ESI-TOF) n/z calcd. for C₃₇H₄₆N₅O₅ ([M+H]⁺)640.34935, found 640.35003.

cyclo-[(Me)Aba(4-iBu)-Phe-Leu-Ala-Phe] (SEQ ID NO: 26)

Prepared following the general procedure outlined above usingacryloyl-Phe-Leu-Ala-Phe-(Me)Leu (SEQ ID NO: 27)(6.8 mg, 10 μmol, 1.0equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1.3 mg, 1.2 μmol, 0.12 equiv.),K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMF (2.0 mL). After 10 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 77%, 1.6:1 dr. ¹H NMR (500 MHz,CD₃OD) Major diastereomer: 8 7.32-7.16 (m, 10H), 4.82 (dt, J=9.3, 6.1Hz, 1H), 4.69-4.62 (m, 1H), 4.54 (tt, J=11.0, 4.1 Hz, 1H), 4.17 (p,J=6.9 Hz, 1H), 3.98-3.91 (m, 1H), 3.08-3.03 (m, 2H), 2.92 (dd, J=13.6,7.2 Hz, 1H), 2.62 (s, 3H), 2.23-2.08 (m, 2H), 1.85-1.73 (m, 2H), 1.57(ddd, J=14.2, 9.9, 4.7 Hz, 1H), 1.44-1.32 (m, 4H), 1.32-1.25 (m, 1H),1.20 (tt, J=11.1, 6.1 Hz, 1H), 1.02-0.94 (m, 1H), 0.93-0.72 (m, 14H);Minor diastereomer: 6 7.34-7.15 (m, 10H), 4.49 (q, J=6.8 Hz, 1H), 4.32(q, J=7.1, 6.0 Hz, 2H), 4.0 (t, J=7.5 Hz, 1H), 3.89 (dd, J=11.2, 4.3 Hz,1H), 3.24-3.15 (m, 1H), 3.08 (d, J=8.0 Hz, 2H), 2.98-2.91 (m, 1H), 2.67(s, 3H), 2.33 (dd, J=15.8, 7.6 Hz, 1H), 2.15 (dd. J=15.8, 9.8 Hz, 1H),1.95-1.84 (m, 1H), 1.78 (td, J=13.0, 11.3, 4.4 Hz, 1H), 1.63 (ddd,J=14.4, 10.3, 4.7 Hz, 2H), 1.41 (d, J=7.0 Hz, 3H), 1.40-1.19 (m, 4H),0.93-4.77 (m, 12H); HRMS (ES-TOF) m/z calcd. for C₃₆H₅₂N₅O₅ ([M+H]⁺)634.39630, found 634.39733.

cyclo[(3-Ac)pa-Phe-Leu-Ala-Phe] (SEQ ID NO: 28)

Prepared following the general procedure outlined above usingacryloyl-Phe-Leu-Ala-Phe-Acc (SEQ ID NO: 29) (6.3 mg, 10 μmol, 1.0equiv.), Ir[d(CF₃)ppy]₂(dtbbpy)PF₆ (13 mg, 1.2 μmol, 0.12 equiv.), K₂PO₄(3.5 mg, 20 μmol, 2.0 equiv.), and DMSO (4.0 mL). After 12 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12 minutes.Reaction yield was determined to be 48%. ¹H NMR (500 MHz, CD₃OD)) δ7.33-7.19 (m, 10H), 4.70 (t, J=7.9 Hz, 1H), 4.09 (dd, J=9.4, 6.3 Hz,1H), 3.84 (q, J=7.3 Hz, 1H), 3.75 (dd, J=11.3, 4.2 Hz, 1H), 3.07 (dd,J=13.7, 8.2 Hz, 1H), 2.97 (dd, J=13.7, 7.51 Hz, 1H), 2.34-2.28 (m, 1H),2.05 (d, J=14.3 Hz, 1H), 1.95-1.81 (m, 2H), 1.43 (ddd, J=13.7, 10.0, 4.3Hz, 1H), 1.34-1.16 (m, 6H), 0.98-0.92 (m, 2H), 0.91 (d, J=6.6 Hz, 3H),0.83 (d, J=6.5 Hz, 3H), 0.72 (ddd, J=10.6, 6.2, 4.4 Hz, 1H), 0.67-0.54(m, 2H); HRMS (ESI-TOF) m/z calcd. for C₃₃H₄₄N₅O₅ ([M+H]⁺) 590.33370,found 590.33304.

cyclo[(3-Aep)pa-Phe-[Leu-Aa-Phe] (SEQ ID NO: 30)

Prepared following the general procedure outlined above usingacryloyl-Phe-Leu-Ala-Phe-Aepe (SEQ ID NO: 31) (6.6 mg, 10 μmol, 1.0equiv.). Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (13 mg, 1.2 μmol, 0.12 equiv.),K₂PO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMSO (4.0 mL). After 12 h, thereaction mixture was removed from LED irradiation, centrifuged, andsubjected to HPLC analysis. Conditions: Vydac 218TP C18 5μ, length 150mm, ID 4.6 mm, 40-80% MeCN/H₂O 0.1% formic acid over 12 minutes.Reaction yield was determined to be 49%. ¹H NMR (500 MHz, CD₃OD) S7.33-7.18 (m, 10H), 4.65 (t, J=7.8 Hz, 1H), 4.16 (dd, J=11.1, 4.7 Hz,1H), 3.94 (q, J=7.2 Hz, 1H), 3.68 (dd, J=11.4, 4.1 Hz, 1H), 3.31-3.27(m, 1H), 3.22 (dd, J=13.9, 11.2 Hz, 1H), 3.07-2.96 (m, 2H), 2.36-2.28(m, 2H), 227-2.16 (m, 2H), 2.15-2.09 (m, 1H), 2.09-2.02 (m, 1H), 1.90(ddd, J=13.3, 11.3, 4.2 Hz, 1H), 1.83-1.73 (m, 1H), 1.64-1.51 (m, 3H),1.51-1.41 (n, 3H), 1.27 (d, J=7.3 Hz, 3H), 1.19-1.09 (m, 1H), 0.89 (d,J=6.5 Hz, 3H), 0.79 (d, J=6.4 Hz, 3H); HRMS (ESI-TOF) m/z calcd. forC₃₅H₄₇N₅O₅ ([M+H]⁺) 618.36500, found 618.36465.

cyclo-[Aha-Ala-Tyr(tBu)]

Prepared following the general procedure outlined above usingacryloyl-Ala-Tyr(tBu)-Gly (0.42 mg, 1 μmol, 1.0 equiv.),Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (0.22 mg, 0.2 μmol, 0.20 equiv.), K₂H PO₄(0.35 mg, 2.0 μmol, 2.0 equiv.), 2, 4, 6-triisopropylbenzenethiol (0.024mg, 0.1 μmol, 0.1 equiv.), and DMF (1.0 mL). After 12 h, the reactionmixture was removed from LED irradiation and concentrated. The residuewas then dissolved in 100 μL DMF, centrifuged, and subjected to HPLCanalysis. Conditions: Vydac 218TP C18 5μ, length 150 mm, ID 4.6 mm,10-50% MeCN/H₂O+0.1% formic acid over 12 minutes. Reaction yield wasdetermined to be 24%. ¹H NMR. (500 MHz, CD₃OD) ) 7.21 (d. J=8.0 Hz, 2H),6.93 (d, J=7.61 Hz, 3H), 4.68 (br s, 1H), 4.03 (br s, 1H), 3.80 (br s,1H), 3.02-2.86 (m, 2H), 2.86-2.79 (m, 1H), 2.26-2.17 (m, 1H), 2.19-2.04(m, 21), 1.83-1.73 (m, 1H), 1.32 (s, 9H), 1.13 (d. J=6.5 Hz, 3H); HRMS(ESI-TOF) m/z calcd, for C₂H₃₀N₃O₄ ([M+H]⁺) 376.22308, found 376.22297.

cyclo-[Aba-Phe-Leu-Ala-Phe](SEQ ID NO: 32)

Prepared following the general procedure outlined above usingacryloyl-Phe-Ala-Pro-Glu(OtBu)-Leu-Phe-Ala-Gly (SEQ ID NO: 33) (9.6 mg,10 μmol, 1.0 equiv.), Ir[dF(CF₃)ppy]2(dtbbpy)PF₆ (0.9 mg, 0.8 μmol, 0.08equiv.), K₂HPO₄ (3.5 mg, 20 μmol, 2.0 equiv.), and DMF (2.0 mL). After10 h, the reaction mixture was removed from LED irradiation,centrifuged, and subjected to HPLC analysis. Conditions: Vydac 218TP C185μ, length 150 mm, 1H) 4.6 mm, 40-80% MeCN/H₂O+0.1% formic acid over 12minutes. Reaction yield was determined to be 61%. ¹H NMR (500 MHz,CD₃OD) δ 7.31-7.15 (m, 10H), 4.70 (dt, J=10.6, 3.0 Hz, 1H), 4.61 (d,J=9.1 Hz, 1H), 4.52 (t. J=7.41 Hz, 1H), 4.40-4.30 (m, 1H), 4.15-4.06 (m,1H), 4.04-3.98 (m, 1H), 3.63 (br s, 1H), 3.60-3.48 (m, 1H), 3.42-3.35(m, 1H), 3.23-3.08 (m, 1H), 3.04 (q, J=6.8 Hz, 1H), 2.91 (br s, 1H),2.87-2.72 (m, 1H), 2.54-2.48 (m, 1H), 2.46-2.37 (m, 1H), 2.36-2.14 (m,3H), 2.13-1.72 (m, 8H), 1.66 (t, J=12.6.Hz, 1H), 1.54-1.43 (m, 9H),1.39-1.24 (m, 8H), 0.96-0.77 (m, 6H); HRMS (ES-TOF) m/z calcd. forC₄₈H₆₉N₈O₁₀ ([M+H]⁺) 917.51312, found 917.51229.

cyclo-[Aba-Ala-Phe-Leu-Pro-Ala-Thr(tBu)-Val-Tyr(tBu)-Leu] (SEQ ID NO:34)

Prepared following the general procedure outlined above usingacryloyl-Ala-Phe-Leu-Pro-Aa-Thr(tBu)-Val-Tyr(tBu)-Leu-Gly (SEQ ID NO:35) (3.1 mg, 2.5 μmol, 1.0 equiv.), Ir[dF(CF₃)ppy]2(dtbbpy)PF₆ (0.33 mg,0.3 μmol, 0.12 equiv.), K₂HPO₄ (0.88 mg, 5 μmol, 2.0 equiv.), and DMF(1.0 mL). After 20 h, the reaction mixture was removed from LEDirradiation, centrifuged, and subjected to HPLC analysis. Conditions:Vydac 218TP C18 5μ, length 150 mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1%formic acid over 12 minutes. Reaction yield was determined to be 64%(n=2). ¹H NMR (500 MHz, CD₃OD) NMR spectrum is complicated by thepresence of rotamers. δ 7.29-7.19 (m, 5H), 7.18-7.14 (m, 2H), 6.87 (d,J=8.4 Hz, 2H), 4.82 (q, J=7.2 Hz, 1H), 4.71 (q, J=7.7 Hz, 1H), 4.68-4.62(m, 1H), 4.58-4.47 (m, 1H), 4.39 (t, J=7.1 Hz, 1H), 4.34 (t, J=4.6 Hz,1H), 4.32-4.24 (m, 2H), 4.12 (q, J=7.0 Hz, 1H), 3.81-3.74 (m, 1H), 3.66(q, J=9.3, 8.6 Hz, 1H), 3.46 (dt, J=9.9, 6.9 Hz, 1H), 3.17 (ddd, J=13.5,7.7, 5.1 Hz, 2H), 3.03-2.88 (m, 2H), 2.45-2.35 (m, 1H), 2.28 (ddd,J=15.4, 9.8, 6.7 Hz, 2H), 2.15 (ddd, J=14.0, 9.9, 5.6 Hz, 2H), 1.99 (t,J=14.4, 6.7 Hz, 3H), 1.94-1.76 (m, 3H), 1.76-1.61 (m, 4H), 1.59 (t,J=7.1 Hz, 2H), 1.46 (d, J=7.2 Hz, 2H), 1.31 (s, 9H), 1.29 (s, 9H),1.04-0.86 (m, 18H), 0.82 (dd. J=16.3, 6.7 Hz, 6H); HRMS (ES-TOF) m/zcalcd. for C₆₂H₉₇N₁₀O₁₂ ([M+H]⁺) 1173.72820, found 1173.72778.

cyclo-[Aba-Ala-Leu-Pbe-Lys(Boc)-Pro-Ala-Phe-Ala-Leu-Pro-Glu(OBu)-Leu-Phe-VaI](SEQ ID NO: 36)

Prepared following the general procedure outlined above usingacryloyl-Ala-Leu-Phe-Lys(Boc)-Pro-Ala-Phe-Ala-Leu-Pro-Glu(OtBu)-Leu-Phe-Val-Gly(SEQ ID NO: 37)(1.83 mg, 1 μmol, 1.0 equiv.), Ir[dF(CF₃)ppy]₂(dtbbpy)PF(0.22 mg, 0.2 μmol, 0.2 equiv.), K₂HPO₄ (0.35 mg, 2.0 μmol, 2.0 equiv.),and DMF (4.0 mL). After 20 h, the reaction mixture was removed from LEI)irradiation, centrifuged, and subjected to HPLC analysis. Conditions:Vydac 218TP C18 5μ, length 150 mm, ID 4.6 mm, 40-80% MeCN/H₂O+0.1%formic acid over 12 minutes. Reaction yield was determined to be 60%. ¹HNMR (500 MHz, CD₃OD) δ 7.37-7.02 (15H), 4.76 (1H), 4.74 (1H), 4.71 (1H),4.68 (1H), 4.64 (1H), 4.49 (1H), 4.44 (1H), 4.360 (1H), 4.34 (1H), 4.23(1H), 4.04 (1H), 3.93 (1H), 3.86 (1H), 3.77 (1H), 3.65 (2H), 3.50 (2H),3.16 (2H), 3.07 (2H), 2.93 (2H), 2.68-2.60 (2H), 2.40 (1H), 2.31 (1H),2.14 (1H), 2.09 (2H), 2.02 (1H), 1.98 (2H), 1.90 (2H), 1.88 (2H), 1.84(2H), 1.83-1.75 (2H), 1.77 (3H), 1.65 (2H), 1.63 (2H), 1.56 (2H), 1.51(2H), 1.46 (2H), 1.45 (9H), 1.44 (4H), 1.39 (9H), 1.35 (3H), 1.28 (3H),1.23 (3H), 0.99 (6H), 0.97 (6H), 0.91 (6H), 0.85 (6H); HRMS (ESI-TOF)m/z calcd. for C₉₃H₁₄₂N₁₆O₁₉ ([M+2H]²⁺) 893.53187, found 893.53163.

General Procedure for Decarboxylative Conjugate Coupling

Commercial reagents were purchased from Sigma Aldrich and purified priorto use following the guidelines of Perrin and Armarego, Purification ofLaboratory Chemicals, Pergamon, Oxford, ed. 3 1988) (hereinafter“Perrin”). All solvents were purified by passage through columns ofactivated alumina. Organic solutions were concentrated under reducedpressure on a Büchi rotary evaporator using an acetone-dry ice bath forvolatile compounds. Chromatographic purification of products wasaccomplished by flash chromatography on silica gel (Fluka, 230-400mesh). Thin layer chromatography (TLC) was performed on AnaltechUniplate 250 m silica gel plates. Visualization of the developedchromatogram was performed by fluorescence quenching, p-anisaldehyde,potassium permanganate, or ceric ammonium molybdate stain. ¹H and ₁₃CNMR spectra were recorded on a Bruker 500 (500 and 125 MHz) instrument,and are internally referenced to residual protio solvent signals (note:CDCl₃ referenced at 7.26 and 77.0 ppm respectively). Data for ¹H NMR arereported as follows: chemical shift (6 ppm), integration, multiplicity(s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), couplingconstant (Hz) and assignment. Data for ¹³C NMR are reported in terms ofchemical shift and no special nomenclature is used for equivalentcarbons. High resolution mass spectra were obtained at PrincetonUniversity mass spectrometry facilities. All amino acids were used fromcommercial suppliers. All aryl and heteroaryl halides were used fromcommercial suppliers or prepared using standard literature procedures.

An oven-dried 8 mL vial equipped with a Teflon septum and magnetic stirbar was charged with Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2 μmol, 0.01 equiv),Cbz-Pro-OH (0.2 mmol, 1.0 equiv), diethyl ethylidenemalonate (0.2 mmol,1.0 equiv), K₂HPO₄ (0.24 mmol, 1.2 equiv), and 0.5 mL of DMF. Thereaction mixture was degassed by bubbling nitrogen stream for 15 min,then irradiated with a 26 W fluorescent lamp (at approximately 2 cm awayfrom the light source). After 36 h, the reaction mixture was dilutedwith saturated aqueous NaHCO₃ solution, extracted with Et₂O (3×50 mL).The combined organic extracts were washed with water and brine, driedover MgSO₄ and concentrated in vacuo. Purification of the crude productby flash chromatography on silica gel using the indicated solvent systemafforded the desired product.

(±)-Benzyl 2-(3-oxocyclopentyl)pyrrolidine-1-carboxylate: According tothe general procedure. Ir[dF(CF₃)ppy)]₂(dtbbpy)PF (2.2 mg, 2 μmol, 0.01equiv.), Cbz-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv), 2-cyclopenten-1-one(16.4 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24 mmol, 1.2 equiv),and 0.5 mL of DMF were used. The product was isolated by flashchromatography (20% ethyl acetate/hexane) as a pale yellow oil (51 mg,88%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers and rotamers: δ7.37-7.30 (m, 51), 5.16-5.10 (m, 2H), 4.06-3.96 (m, 1H), 3.62-3.52 (m,1H), 3.38 (br, 1H), 2.35-1.79 (m, 10H), 1.69-1.64 (m, 1H); ¹³C NMR (125MHz, CDCl₃) mixture of diastereomers and rotamers: δ 218.79, 218.42,155.93, 155.85, 155.62, 155.45, 136.97, 136.55, 128.57, 128.41, 128.25,128.02, 127.84, 67.22, 66.82, 60.90, 60.76, 60.27, 60.18, 46.75, 46.66,42.84, 42.08, 41.65, 41.46, 41.35, 38.70, 38.52, 38.34, 29.49, 28.88,28.54, 28.13, 26.82, 26.12, 24.04, 23.96, 23.12, 23.04; HRMS (ESI) m/zcalcd for C₁₇H₂₂NO₃ [(M+H)⁺] 288.1600, found 288.1609, IR (film) 2961,1738, 1693, 1405, 1102, 698 cm−¹.

(t)-Benzyl 2-(3-oxo-2,3-diphenylpropyl)pyrrolidine-1-carboxylate:According to the general procedure. Ir[dF(CF₃)ppy)](dtbbpy)PF (2.2 mg, 2μmol, 0.01 equiv.), Cbz-Pro-OH (49.9 mg, 0.2 mmol, 1.0 equiv.). CsF(36.5 mg, 0.24 mmol, 1.2 equiv.), 1,2-diphenylprop-2-en-1-one (41.7 mg,0.2 mmol, 1.0 equiv.) and DMF (0.5 mL) were used. The product wasisolated by flash chromatography (30% ethyl acetate in hexanes) as acolourless powder (67 mg, 81%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 8.06-7.84 (m, 2H), 7.50-7.14 (m, 13H),5.20-5.03 (m, 1.2H), 5.03-4.90 (m, 0.6H), 4.82-4.75 (m, 0.2H), 4.74-4.67(m, 0.2H), 4.67-4.58 (m, 0.6H), 4.41 (d, J=12.5 Hz, 0.2H), 4.26-4.18 (m,0.4H), 4.05-3.94 (m, 0.35H), 3.94-3.85 (m, 0.25H), 3.55-3.20 (m, 2H),2.79-2.67 (m, 0.5H), 2.41-2.32 (m, 0.15H), 2.30-2.21 (m, 0.2H),2.21-1.71 (m, 4.5H), 1.55-1.44 (m, 0.65H); ¹³C NMR (125 MHz, CDCl₃)mixture of diastereomers and rotamers: δ 199.40, 199.15, 198.95, 198.57,155.43, 155.28, 154.93, 139.86, 139.70, 139.52, 139.31, 137.28, 136.87,136.79, 136.60, 136.46, 136.40, 132.87, 132.73, 132.60, 129.05, 128.96,128.88, 128.77, 128.63, 128.52, 128.47, 128.38, 128.24, 128.14, 128.06,127.86, 127.81, 127.69, 127.11, 126.99, 66.86, 66.53, 66.48, 56.49,56.20, 55.64, 51.09, 50.89, 50.39, 46.45, 46.25, 45.76, 40.15, 39.58,39.05, 31.77, 31.41, 31.26, 30.99, 23.83, 23.55, 22.90; HRMS (ESI) n/zcalcd for C₂₇H₂₈NO₃ [(M+H)⁺] 414.20637, found 414.20623. IR (film) 2958,1686, 1407, 1353, 1206, 1177, 1096, 953, 747, 694 cm⁻¹.

(±)-Benzyl 2-(4-oxobutan-2-yl)pyrrolidine-1-carboxylate: According tothe general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (11 mg, 10.0 μmol,0.01 equiv), Cbz-Pro-H (250.0 mg, 1.0 mmol, 1.0 equiv), crotonaldehyde(70.9 mg, 1.0 mmol, 1.0 equiv), K₂HPO₄ (210.0 mg, 1.2 mmol, 1.2 equiv),and 2.5 mL of DMF were used. The product was isolated by flashchromatography (20% ethyl acetate/hexane) as a pale yellow oil (253 mg,92%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers and rotamers: δ9.70 (br, 0.3H), 9.59-9.57 (m, 0.5H), 9.50 (br, 0.2H), 7.37-7.30 (m,5H), 5.16-5.09 (m, 2H), 3.90 (br, 0.55H), 3.81 (br, 0.45H), 3.65-3.48(m, 1H), 3.31-3.26 (m, 0.45H), 3.22-3.17 (m, 0.55H), 2.95 (br, 0.3H),2.69 (br, 0.2H), 2.59-2.49 (m, 0.6H), 2.39-2.34 (m, 0.6H), 2.26-2.11 (m,0.9H), 1.93-1.63 (m, 4.4H), 0.96-0.86 (m, 3H); ¹³C NMR (125 MHz, CDCl₃)mixture of diastereomers and rotamers: δ 202.10, 201.83, 201.61, 201.42,155.43, 155.38, 155.16, 136.78, 136.52, 128.32, 127.93, 127.76, 127.60,66.87, 66.54, 61.91, 61.66, 61.00, 47.93, 47.66, 47.20, 47.08, 46.61,46.16, 45.77, 31.06, 30.98, 30.96, 30.37, 27.19, 26.82, 25.79, 24.18,23.85, 23.55, 23.24, 16.91, 15.68, 15.25; HRMS (ESI) m/z calcd forC₁₆H₂₁NNaO₃ [(M+Na)⁺] 298.1419, found 298.1422. IR (film) 2962, 1692,1404, 1097, 697 cm⁻¹.

(±)-2-Benzyl-3-(1-((benyloxy)carbonyl)pyrrolidin-2-yl)propanoic acid:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PFs (2.2 mg,2 μmol, 0.01 equiv.), Cbz-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv),2-benzylacrylic acid (32.4 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg,0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product wasisolated by flash chromatography (50% ethyl acetate/hexane) as a paleyellow solid (42 mg, 57%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiasteromers and rotamers: δ 7.41-7.08 (m, 10H), 5.23-5.01 (m, 2H),4.16-4.12 (m, 0.6H), 3.98-3.92 (m, 0.4), 3.46-3.42 (m, 1H), 3.32-3.27(m, 1H), 3.12-2.60 (m, 3H), 2.20-1.53 (m, 6H; ¹³C NMR (125 MHz, CDCl₃)mixture of diastereomers and rotamers: δ 179.80, 179.56, 177.13, 157.21,155.39, 155.22, 139.26, 139.05, 138.75, 138.70, 136.90, 136.36, 129.37,129.16, 129.04, 128.96, 128.71, 128.57, 128.53, 128.42, 128.34, 128.17,128.04, 127.97, 126.62, 126.53, 126.45, 67.82, 67.11, 66.97, 56.24,55.93, 55.63, 46.66, 46.45, 46.28, 44.89, 44.58, 44.43, 38.85, 38.56,38.42, 36.75, 36.37, 36.04, 31.53, 31.24, 30.82, 30.40, 29.83, 23.71,23.47, 23.16, 22.93; HRMS (ESI) m/z calcd for C₂₂H₂₆NO₄ [(M+H)⁺]1368.1862, found 368.1868. IR (film) 2957, 1700, 1419, 1105, 698 cm⁻¹.

(±)-Benzyl 2-(4-benzamido-4-oxobutan-2-yl)pyrrolidine-1-carboxylate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Cbz-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv),(E)-N(but-2-enoyl)benzamide (37.8 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0mg, 0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product wasisolated by flash chromatography (30% ethyl acetate/hexane) as a paleyellow solid (67 mg, 85%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 9.41 (s, 0.2H), 9.03 (s, 0.4H), 8.45 (s,0.14H), 8.39 (m, 0.26H), 7.91-7.78 (m, 2H), 7.62-7.56 (m, 1H), 7.51-7.45(m, 2H), 7.37-7.22 (m, 5H), 5.16-5.0 (m, 2H), 4.04 (br, 0.2H), 3.92-3.91(m, 0.8H), 3.68-3.59 (m, 0.6H), 3.55-3.50 (m, 0.4H), 3.36-3.29 (m, 1H),3.09-2.88 (m, 1H), 2.81-2.68 (m, 1H), 2.61-2.49 (m, 1H), 2.00-1.73 (m,41), 1.02-0.93 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 175.46, 175.21, 174.58, 174.23, 165.63,165.57, 156.11, 155.93, 155.76, 155.57, 136.98, 136.89, 133.25, 133.03,129.02, 128.86, 128.57, 128.52, 128.46, 128.12, 127.96, 127.84, 127.77,67.00, 66.91, 66.81, 62.15, 61.37, 61.32, 47.83, 47.32, 46.80, 41.74,41.40, 40.01, 34.02, 32.73, 32.50, 27.82, 27.71, 27.45, 24.42, 24.02,23.77, 23.51, 17.00, 16.59, 15.84, 15.60; HRMS (ESI) m/z calcd forC₂₃H₂₇N₂O₄ [(M+H)] 395.1971, found 395.1961. IR (film) 2964, 1686, 1411,1242, 1102, 705 cm⁻¹.

(±)-Benzyl 2-(2-(phenylsulfonyl)ethyl)pyrrolidine-1-carboxylate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Cbz-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv), phenylvinylsulfone (33.6 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24 mmol,1.2 equiv), and 0.5 mL of DMF were used. The product was isolated byflash chromatography (50% ethyl acetate/hexane) as a pale yellow solid(52 mg, 69%). ¹H NMR (500 MHz, CDCl₃) mixture of diasteromers androtamers: 6 7.90 (d, J=7.5 Hz, 1H), 7.83 (d, J=7.0 Hz, 1H), 7.65 (t,J=7.5 Hz, 1H), 7.57-7.52 (m, 21H), 7.33-7.30 (m, 4H), 7.26-7.22 (m, 1H),5.09-5.04 (m, 2H), 3.96-3.89 (m, 1H), 3.49-3.35 (m, 2H), 3.20 (d, J=8.0Hz, 1H), 3.03-3.02 (m, 1H), 2.09-1.94 (m, 2H), 1.90-1.82 (m, 3H),1.65-1.62 (m, 1H); ¹³ NMR (125 MHz, CDCl₃) mixture of diastereomers androtamers: δ 155.47, 155.00, 139.20, 139.02, 136.81, 136.39, 133.78,129.37, 128.64, 128.57, 128.22, 128.10, 128.06, 127.87, 67.20, 66.85,56.49, 55.87, 53.93, 53.60, 46.87, 46.48, 31.14, 30.68, 27.90, 27.83,23.75, 23.02: HRMS (ES) n/z calcd for C₂₀H₂₄NO₄S [(M+H)⁺] 374.1426,found 374.1431. IR (film) 2956, 1691, 1408, 1304, 1143, 1086, 742 cm⁻¹.

(±)-Diethyl 2-(1-(1-benzoylpyrrolidin-2-yl)ethyl)malonate: According tothe general procedure, Ir[dF(CF₃)ppy)]₂(dbbpy)PF₆ (2.2 mg, 2 μmol, 0.01equiv.), Cbz-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv), dimethyl maleate(28.8 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24 mmol, 1.2 equiv),and 0.5 mL of DMF were used. The product was isolated by flashchromatography (25% ethyl acetate/hexane) as a pale yellow oil (65 mg,93%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers and rotamers: δ7.41-7.29 (m, 5H), 5.21-5.08 (m, 2H), 4.31-4.28 (m, 0.55H), 4.17-4.09(m, 0.45H) 3.69-3.64 (m, 6.811), 3.56-3.47 (m, 0.8H), 3.37-3.33 (m,0.81), 3.28-3.22 (m, 0.61) 2.81-2.70 (m, 1H), 2.54-2.29 (m, 1H),1.95-1.72 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers androtamers: δ 173.60, 173.27, 173.03, 172.37, 172.30, 172.14, 155.40,155.03, 136.89, 136.77, 136.56, 128.52, 128.22, 128.08, 128.03, 127.99,127.86, 67.22, 66.86, 59.02, 58.35, 58.24, 57.42, 52.13, 52.11, 51.92,51.86, 47.79, 47.19, 46.96, 46.60, 44.57, 44.31, 44.13, 43.65, 33.60,31.15, 30.54, 28.14, 28.10, 27.42, 24.17, 23.64, 23.57, 22.85; HRMS(ESI) m/z calcd for C₁₈H₂₄NO₆ [(M+H)]⁺ 350.1604, found 350.1600. IR(film) 2953, 1697, 1732, 1408, 1165, 1110, 699 cm⁻¹.

(±)-Benzyl 2-(3-(benzyloxy)-3-oxopropyl)pyrrolidine-1-carboxylate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Cbz-Pro-OH (49.9 mg, 0.2 mmol, 1.0 equiv.), benzylacrylate (32.4 mg, 0.2 mmol, 1.0 equiv.), K₂HPO₄ (41.8 mg, 0.24 mmol,1.2 equiv.) and DMF (0.5 mL) were used. The product was isolated byflash chromatography (30% ethyl acetate in hexanes) as a colorless oil(55 mg, 75%). ¹H NMR (500 MHz, CDCl₃) mixture of rotamers: δ 7.31-7.19(m, 10H), 5.08-4.94 (m, 4H), 3.89-3.80 (m, 1H), 3.46-3.26 (m, 2H),2.40-2.22 (m, 2H), 2.05-1.95 (m, 0.5H), 1.95-1.62 (m, 4.5H), 1.60-1.50(m, 1H); ¹³C NMR (125 MHz, CDCl₃) mixture of rotamers: δ 173.25, 173.03,155.14, 137.03, 136.84, 136.01, 135.94, 128.54, 128.46, 128.26, 128.20,127.97, 127.88, 127.85, 66.84, 66.59, 66.28, 57.25, 56.54, 46.65, 46.32,31.36, 31.17, 30.75, 30.05, 29.80, 29.44, 23.77, 23.00; HRMS (ESI) m/zcalcd for C₂₂H₂₆NO₄ [(M+H)⁺] 368.18563, found 368.18568. IR (film) 2957,1733, 1695, 1455, 1409, 1355, 1165, 1151, 1098, 743, 697 cm⁻¹.

(±)-Benzyl 2-(3-butoxy-2-methyl-3-oxopropyl)pyrrolidine-1-carboxylate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Cbz-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv), butylmethacrylate (28.4 mg, 0.2 mmol, 1.0 equiv). K₂HPO₄ (42.0 mg, 0.24 mmol,1.2 equiv), and 0.5 mL of DMF were used. The product was isolated byflash chromatography (20% ethyl acetate/hexane) as a pale yellow oil (48mg, 69%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers and rotamers:6 7.39-7.26 (m, 5H), 5.18-5.07 (m, 2H), 4.06-3.91 (m, 3H), 3.49-3.33 (m,2H), 2.56-2.38 (m, 1H), 2.18-1.60 (m, 6H), 1.39-1.31 (m, 3H), 1.24-1.20(m, 1.4H), 1.10-1.09 (m, 2H), 0.95-0.90 (m, 3.6H); ¹³C NMR (125 MHz,CDCl₃) mixture of diastereomers and rotamers: δ 176.76, 176.38, 155.28,155.02, 154.69, 137.25, 137.17, 136.94, 128.55, 128.53, 128.29, 128.07,128.01, 127.96, 127.94, 127.93, 127.83, 66.95, 66.91, 66.90, 66.65,66.61, 64.65, 64.33, 64.31, 55.92, 55.45, 46.57, 46.45, 46.28, 46.26,46.20, 38.98, 38.52, 37.49, 37.17, 30.73, 30.71, 30.69, 30.57, 23.89,23.81, 22.99, 19.37, 19.25, 19.24, 17.95, 17.80, 13.89, 13.86, 13.85;HRMS (ESI) m/z calcd for C₂₀H₃₀NO₄ [(M+H]⁺) 348.2175, found 348.2183. IR(film) 2959, 1698, 1408, 1110, 697 cm⁻¹.

(±)-Benzyl 2-(3-methoxy-3-oxo-2-phenylpropyl)pyrrolidine-1-carboxylate:According to the general procedure, Ir[dF(CF)ppy)]₂(dtbbpy)PF₆ (2.2 mg,10.0 μmol, 0.01 equiv) Cbz-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv), methyl2-phenylacrylate (32.4 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (20% ethyl acetatehexane) as a pale yellow oil(65 mg, 89%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers androtamers: δ 7.46-7.15 (m, 10H), 5.15-5.03 (m, 2H), 3.99-3.31 (s, 7H),2.59-2.55 (br, 0.7H), 2.34-2.22 (m, 0.3H), 2.10-2.05 (m, 0.3H),1.91-1.70 (m, 3.7H), 1.57-1.48 (m, 0.8H), 1.27-1.20 (m, 0.2H); ¹³C NMR(125 MHz, CDCl₃) mixture of diastereomers and rotamers: δ 174.25,174.00, 173.91, 155.26, 155.12, 155.01, 139.40, 139.12, 138.57, 138.14,137.04, 136.90, 136.82, 128.71, 128.53, 128.43, 128.38, 128.36, 128.06,127.94, 127.84, 127.39, 127.31, 126.67, 67.04, 66.96, 66.65, 66.59,56.52, 56.06, 55.97, 55.24, 56.52, 56.06, 55.97, 55.24, 52.14, 52.09,48.97, 48.75, 46.60, 46.35, 46.05, 38.68, 38.60, 37.62, 37.24, 31.15,30.80, 30.70, 30.15, 23.88, 23.72, 23.07, 22.90; HRMS (ESI) m/z calcdfor C₂₂H₂₆NO₄ [(M+H)⁺] 368.1862, found 368.1869. IR (film) 2952, 2693,1408, 1097, 697 cm⁻¹.

(±)-Benzyl2-(3-methoxy-2-(4-methoxyphenyl)-3-oxopropyl)pyrrolidine-1-carboxylate:According to the general procedure, Ir[dF(CF₃)ppy)]2(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.) Cbz-Pro-OH (49.9 mg, 0.2 mmol, 1.0 equiv.), CsF(36.5 mg, 0.24 mmol, 1.2 equiv.), methyl 2-(4-methoxyphenyl)acrylate(38.4 mg, 0.2 mmol, 1.0 equiv.) and DMF (0.5 mL) were used. The productwas isolated by flash chromatography (30% ethyl acetate in hexanes) as acolorless oil (60 mg, 76%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 7.50-7.28 (m, 6H), 7.16 (d, J=7.5 Hz,0.8H), 7.08 (d, J=7.5 Hz, 0.2H), 6.90-6.81 (m, 1.8H), 6.71 (d, J=8.5 Hz,0.2H), 5.21-5.05 (m, 2H), 4.04-3.89 (m, 0.8H), 3.85-3.75 (m, 3.5H),3.75-3.52 (m, 3.5H), 3.52-3.30 (m, 2.2H), 2.62-2.49 (m, 0.8H), 2.43-2.33(m, 0.1H), 2.29-2.20 (m, 0.1H), 2.10-1.42 (m, 5H); ¹³C NMR (125 MHz,CDCl₃) mixture of diastereomers and rotamers: δ 174.48, 174.22, 174.15,158.79, 155.20, 155.04, 154.99, 136.99, 136.86, 136.77, 131.36, 131.09,129.03, 128.80, 128.00, 127.88, 127.78, 114.00, 66.97, 66.60, 56.43,55.93, 55.26, 55.23, 55.10, 52.07 52.00, 48.06, 47.81, 46.55, 46.29,46.02, 38.69, 38.58, 37.36, 36.96, 31.20, 30.79, 30.53, 29.99, 23.84,23.69, 23.03, 22.86; HRMS (ESI) m/z calcd for C₂₃H₂₈NO₅ [(M+H)⁺]398.1962, found 398.19642. IR (film) 2952, 1731, 1694, 1511, 1409, 1351,1248, 1178, 1161, 1097, 1032, 698 cm⁻¹.

(±)-Benzyl2-(2-(2-bromophenyl)-3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Cbz-Pro-OH (49.9 mg, 0.20 mmol, 1.0 equiv.),K₂HPO₄ (41.8 mg, 0.24 mmol, 1.2 equiv.), methyl2-(2-bromophenyl)acrylate (48.2 mg, 0.2 mmol, 1.0 equiv.) and DMF (0.5mL) were used. The product was isolated by flash chromatography (30%ethyl acetate in hexanes) as a colorless oil (77 mg, 87%). ¹H NMR (500MHz, CDCl₃) mixture of diastereomers and rotamers: δ 7.60-7.53 (m, 1H),7.52-7.25 (m, 6.5H), 7.18-6.98 (m, 1.5H), 5.23-5.03 (m, 2H), 4.37-4.20(m, 1H), 4.12-4.03 (m, 0.65H), 3.90-3.83 (m, 0.16H), 3.77-3.75 (m,0.19H), 3.74-3.55 (m, 3H), 3.54-3.33 (m, 2H), 2.71-2.62 (m, 0.3H),2.57-2.47 (m, 0.3H), 2.37-2.28 (m, 0.2H), 2.23-2.16 (m, 0.2H), 2.12-1.60(m, 5H); ¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers and rotamers:δ 173.61, 173.45, 173.30, 173.18, 155.13, 154.99, 154.94, 138.94,138.67, 138.05, 137.74, 137.04, 136.85, 136.78, 133.07, 132.95, 128.97,128.93, 128.77, 128.72, 128.66, 128.49, 128.44, 128.32, 128.29, 128.00,127.81, 124.82, 124.79, 124.34, 66.95, 66.53, 56.61, 55.96, 55.73,55.08, 55.22, 47.73, 47.55, 47.23, 47.06, 46.57, 46.33, 46.27, 46.11,38.20, 37.51, 37.34, 36.89, 30.94, 30.71, 30.27, 30.12, 23.81, 23.76,22.98, 22.88; HRMS (ESI) m/z calcd for C₂₂H₂₅BrNO₄ [(M+H)⁺] 446.09615,found 446.09693. IR (film) 2951, 1734, 1694, 1408, 1350, 1187, 1166,1096, 1022, 748, 697 cm⁻¹.

(±)-Benzyl2-(2-(2,4-difluorophenyl)-3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 mol, 0.01 equiv.), Cbz-Pro-OH (74.8 mg, 0.30 mmol, 1.5 equiv.), K₂HPO₄(52.3 mg, 0.3 mmol, 1.5 equiv.), methyl 2-(2,4-difluorophenyl)acrylate(39.6 mg, 0.2 mmol, 1.0 equiv.) and DMF (0.5 mL) were used. The productwas isolated by flash chromatography (30% ethyl acetate in hexanes) as acolorless oil (73 mg, 90%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 7.55-7.23 (m, 5.9H), 7.11-7.03 (m, 0.3H),6.89-6.70 (m, 1.6H), 6.54 (t, J=8.0 Hz, 0.2H), 5.22-5.03 (m, 2H),4.14-4.06 (m, 0.3H), 4.06-3.93 (m, 1H), 3.93-3.86 (m, 0.2H), 3.82-3.74(m, 0.2H), 3.70-3.57 (m, 3H), 3.54-3.31 (m, 2H), 2.69-2.61 (m, 0.3H),2.58-2.50 (m, 0.3H), 2.45-2.35 (m, 0.2H), 2.28-2.19 (m, 0.2H), 2.11-1.52(m, 5H); IC NMR (125 MHz, CDCl₃) mixture of diastereomers and rotamers:δ 173.32, 173.22, 173.12, 173.04, 163.06, 162.95, 162.87, 161.53,161.44, 161.35, 161.20, 160.97, 159.56, 159.46, 159.37, 159.27, 155.13,155.01, 154.91, 136.92, 136.76, 136.59, 130.37, 130.12, 129.82, 129.66,128.46, 128.27, 128.13, 127.93, 127.83, 127.80, 127.70, 122.56, 122.44,122.27, 122.15, 121.32, 121.20, 120.95, 120.82, 111.85, 11.66, 111.50,111.36, 104.08, 103.95, 103.87, 103.75, 103.67, 103.54, 67.06, 66.61,56.32, 55.76, 54.96, 52.30, 52.24, 46.58, 46.31, 46.14, 41.06, 40.48,40.23, 40.09, 37.76, 37.19, 36.45, 35.89, 31.00, 30.36, 29.82, 23.82,23.75, 23.01, 22.87; HRMS (ESI) n/calcd for C₂₂H₂₄F₂NO₄ [(M+H)⁺]404.16679, found 404.16672.IR(film) 2954, 2883, 1736, 1694, 1503, 1409,1352, 1279, 11%, 1156, 1140, 1098, 964, 850, 698 cm⁻¹.

(±)-Diethyl 2-(1-(1-benzoylpyrrolidin-2-yl)ethyl)malonate: According tothe general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg, 20.0 μmol,0.01 equiv), Cbz-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv), diethyl2-(3-phenylpropylidene)malonate (55.5 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄(42.0 mg, 0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. Theproduct was isolated by flash chromatography (25% ethyl acetate/hexane)as a pale yellow oil (89 mg, 92%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers and rotamers: 6 7.45-7.29 (m, 5H), 7.27-7.23 (m, 2H),7.18-7.04 (m, 3H), 5.20-5.05 (m, 2H), 4.22-3.99 (m, SN), 3.76-3.57 (m,1H), 3.50-3.47 (m, 0.5H), 3.40-3.36 (m, 0.5H), 3.25-3.14 (m, 1H), 3.07(br, 0.611), 2.72-2.38 (m, 2.4H), 2.00-1.95 (m, 1H), 1.91-1.84 (m, 1H),1.82-1.58 (m, 4H), 1.27-1.19 (m, 6H); ³C NMR (125 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 169.02, 168.93, 168.76, 168.61, 155.67,155.35, 142.35, 142.23, 142.00, 141.92, 136.83, 136.76, 136.64, 136.40,128.52, 128.46, 128.40, 128.37, 128.29, 128.22, 128.15, 128.00, 127.92,127.79, 125.89, 67.43, 67.31, 66.93, 66.80, 61.63, 61.42, 61.36, 60.50,59.79, 59.56, 58.88, 54.13, 53.73, 53.37, 52.86, 48.16, 47.74, 47.49,47.01, 42.22, 41.93, 40.58, 34.53, 34.25, 33.04, 32.75, 31.87, 31.75,31.25, 29.77, 29.49, 27.47, 27.24, 24.32, 23.75, 23.65, 23.00, 14.13,14.09, 14.02: HRMS (ESI) m/z calcd for C₂₈H₃₆NO₆ [(M+H)⁺] 482.2543,found 482.2557. IR (film) 2947, 1697, 1405, 1096, 749, 698 cm⁻¹.

(±)-Diethyl2-((1-((benzyloxy)carbonyl)pyrrolidin-2-yl)(cyclohexyl)methyl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]2(dtbbpy)PF₆ (2.2 mg,10.0 μmol, 0.01 equiv), Cbz-Pro)H (50.0 mg, 0.2 mmol, 1.0 equiv),diethyl 2-(cyclohexylmethylene)malonate (50.8 mg, 0.2 mmol, 1.0 equiv),K₂HPO₄ (42.0 mg, 0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. Theproduct was isolated by flash chromatography (25% ethyl acetate/hexane)as a pale yellow oil (80 mg, 87%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 7.47-7.29 (m, 5H), 5.22-5.01 (m, 2H),4.21-4.06 (m, 4H), 3.96-3.87 (m, 0.25H), 3.70-3.53 (m, 1.75H), 3.29-3.17(m, 1H), 3.07-3.00 (m, 1H), 1.97-1.56 (m, 11H), 1.27 (d, J=7.0 Hz, 3H),1.20 (d, J=7.0 Hz, 3H), 1.13-0.96 (m, 5H); ³C NMR (125 MHz, CDCl₃)mixture of diastereomers and rotamers: δ 169.69, 169.63, 169.53, 169.03,168.73, 156.83, 155.73, 155.68, 155.47, 137.04, 136.74, 136.64, 136.06,129.35, 128.53, 128.46, 128.31, 127.98, 127.90, 127.75, 67.87, 67.36,67.00, 66.66, 61.60, 61.43, 61.31, 61.05, 58.35, 57.85, 57.55, 57.06,52.98, 52.71, 51.20, 50.80, 49.67, 49.26, 47.83, 47.72, 47.33, 47.22,45.83, 45.19, 40.27, 40.21, 38.96, 38.70, 33.85, 33.27, 32.02, 31.49,30.86, 28.28, 27.68, 27.63, 27.43, 27.37, 27.05, 26.86, 26.71, 26.59,26.48, 24.40, 23.82, 23.33, 22.42, 14.22, 14.12, 14.00: HRMS (ESI) m/zcalcd for C₂₆H₃₈NO₆ [(M+H)⁺]460.2699, found 460.2697. IR (film) 2926,1698, 1404, 1097, 698 cm⁻¹.

(±)-Diethyl 2-(1-(tetrahydro-2H-pyran-2-yl)ethyl)malonate: According tothe general procedure, Ir[dF(CF₃)ppy)]2(dtbbpy)PF (2.2 mg, 2 mol, 0.01equiv.), tetrahydro-2H-pyran-4-carboxylic acid (26 mg, 0.2 mmol, 1.0equiv), diethyl ethylidenemalonate (37.3 mg, 0.20 mmol, 1.0 equiv),K₂HPO₄ (42.0 mg, 0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. Theproduct was isolated by flash chromatography (10% ethyl acetate/hexane)as a pale yellow oil (50 mg, 90%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers: δ 4.23-4.15 (m, 41), 3.94 (d, J=10.5 Hz, 1H), 3.73 (d,J=5.5 Hz, 0.4H), 3.51 (d, J=9.0 Hz, 0.6H), 3.37-3.26 (m, 1.6H), 3.16 (t,J=9.5 Hz, 0.4H), 2.33-2.27 (m, 1H), 1.87-1.84 (m, 114), 1.74 and 1.72 (2brs, 0.4H), 1.53-1.42 (m, 4H), 1.28-1.17 (m, 6.6H), 1.00-0.97 (m, 3H);³C NMR (125 MHz, CDCl₃) mixture of diastereomers: δ 169.66, 169.11,169.05, 168.88, 79.27, 78.47, 68.69, 68.54, 61.13, 61.08, 60.98, 60.79,54.94, 52.92, 39.03, 38.14, 29.16, 28.65, 26.02, 26.00, 23.71, 23.46,14.16, 14.11, 14.08, 12.88, 11.70; HRMS (ESI) m/z calcd for C₁₄H₂₅O₅[(M+H)⁺] 273.1702, found 273.1703. IR(film) 2939, 1749, 1729, 1088,1029, 895 cm⁻¹.

(±)-Diethyl 2-(1-(tetrahydrofuran-2-yl)ethyl)malonate: According to thegeneral procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg, 2 μmol, 0.01equiv.), tetrahydro-2-furoic acid (24 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (10% ethyl acetate/hexane) as a pale yellow oil(47.5 mg, 92%). ¹H NMR (500 MHz, CDCl₃) mixture of diasteromers: S4.24-4.16 (m, 4H), 3.86-3.68 (m, 3H), 3.61 (d, J=6.0 Hz, 0.55H), 3.42(d, J=9.0 Hz, 0.45H). 2.52-2.45 (m, 0.45H), 2.33-2.26 (m, 0.55H),2.03-1.82 (m, 3H), 1.64-1.57 (m, 1H), 1.28-1.25 (in, 6H), 0.98 (t, J=7.0Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers: δ 169.31,168.86, 168.83, 168.77, 81.25, 80.35, 68.32, 67.75, 61.22, 61.17, 61.09,61.00, 54.93, 54.42, 39.09, 37.36, 30.00, 28.46, 25.98, 25.86, 14.13,14.09, 14.06, 14.05, 13.49, 12.31; HRMS (ESI) m/z calcd for C₁₃H₂₃O₅[(M+H)⁺] 259.1545, found 259.1525. IR (film) 2978, 1748, 1728, 1153,1065, 1030 cm⁻¹.

(±)-Diethyl 2-(1-cyclohexylethyl)malonate [known compound (2)]:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), cycohexanecarboxylic acid (26 mg, 0.2 mmol, 1.0equiv), diethyl ethylidenenalonate (37.3 mg, 0.2 mmol, 1.0 equiv),K₂HPO₄ (42.0 mg, 0.24 mmol, 1.2 equiv), 0.5 mL of DMF and 34 W Blue LED(instead of 26 W fluorescent light bulb) were used. The product wasisolated by flash chromatography (10% ethyl acetate/hexane) as a paleyellow oil (41 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 4.23-4.16 (m, 4H),3.39 (d, J:=9.5 Hz, 1H), 2.21-2.14 (m, 11H), 1.76-1.71 (m, 21-),1.67-1.57 (m, 3H), 1.30-1.08 (m, 11H), 0.98-0.92 (m, 1K), 0.90 (d, J=7.0Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.30, 169.05, 61.14, 61.06, 55.81,40.24, 38.56, 31.52, 27.37, 26.73, 26.53, 26.46, 14.13, 12.89; HRMS(ESI) m/z calcd for C₁₅H₂₆NaO₄ [(M+Na)⁺] 293.1729, found 293.1727. IR(film) 2925, 1753, 1729, 1147, 1031 cm⁻¹.

(±)-Diethyl 2-(1-cyclobutylethyl)malonate: According to the generalprocedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg, 2 μmol, 0.01 equiv.),cyclobutanecarboxylic acid (20 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (54 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.3mmol, 1.2 equiv), 0.5 mL of DMF and 341W Blue LED (instead of 26 Wfluorescent light bulb) were used. The product was isolated by flashchromatography (10% ethyl acetate/hexane) as a pale yellow oil (33 mg,68%). ¹H NMR (500 MHz, CDCl₃) δ 4.20-4.14 (m, 4H), 3.22 (d, J=6.5 Hz,1H), 2.27-2.13 (m, 2H), 2.01-1.89 (m, 2H), 1.83-1.74 (m, 14), 1.72-1.62(m, 3H), 1.27 (t, J=7.5 Hz, 6H), 0.91 (d, J=6.5 z, 3H); ¹³C NMR (125MHz, CDCl₃) δ 169.26, 168.71, 61.16, 60.96, 55.03, 40.10, 39.95, 27.28,27.05, 17.50, 14.14, 14.06, 13.96; HRMS (ESI) m/z calcd for C₁₃H₂₂NaO₄[(M+Na)⁺] 1265.1416, found 265.1400. IR (film) 2970, 1750, 1729, 1148,1032 cm⁻¹.

(±)-Diethyl 2-(1-cyelopentylethyl)malonate: According to the generalprocedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg, 2 μmol, 0.01 equiv.),cyclopentanecarboxylic acid (24 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of 1,4-dioxane were used. The product wasisolated by flash chromatography (10% ethyl acetate/hexane) as a paleyellow oil (30 mg, 58%). ¹H NMR (500 MHz, CDCl₃) δ 4.19 (q, J=7.5 Hz,4H), 3.41 (d, J=6.5 Hz, 1H), 2.17-2.10 (m, 1H), 1.79-1.71 (m, 3H),1.64-1.58 (m, 2H), 1.53-1.50 (m, 2H), 1.27 (td, J=7.5 Hz, J=2.5 Hz, 6H),1.19-1.13 (m, 2H), 1.02 (d, J=7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ169.48, 168.86, 61.15, 60.91, 56.32, 43.82, 38.48, 30.96, 29.66, 25.32,25.28, 14.61, 14.16, 14.10; HRMS (ESI) m/z calcd for C₁₄H₂₅O₄ [(M+H)⁺]257.1753, found 257.1770. IR (film) 2952, 1750, 1728, 1124, 1150, 1030cm⁻¹.

(±)-Diethyl 2-(nonan-2-yl)malonate: According to the general procedure,Ir[dF(CF₃)ppy)]₂(dtbbpy)PF (2.2 mg, 2 μmol, 0.01 equiv.), octanoic acid(29 mg, 0.2 mmol, 1.0 equiv), diethyl ethylidenemalonate (37.3 mg, 0.2mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24 mmol, 1.2 equiv), 0.5 mL of DMFand 34 W Blue LED (instead of 26 W fluorescent light bulb) were used.The product was isolated by flash chromatography (10% ethylacetate/hexane) as a colorless oil (22 mg, 38%). ¹H NMR (500 MHz, CDCl₃)δ 4.19 (q, J=7.0 Hz, 4H), 3.22 (d, J=8.0 Hz, 1H), 2.27-2.19 (m, II),1.42-1.18 (m, 1811), 0.98 (d, J: 7.0 Hz, 3H), 0.87 (t, J: 7.0 Hz, 3H);¹³C NMR (125 MHz, CDCl₃) δ 169.05, 168.89, 61.12, 61.06, 57.84, 34.34,33.39, 31.83, 29.59, 29.24, 26.81, 22.66, 16.96, 14.14, 14.12, 14.11;HRMS (ESI) m/z calcd for C₁₆H₃₀NaO₄ [(M+Na)⁺] 309.2036, found 309.2026.IR (film) 2927, 1753, 1731, 1148, 1031 cm⁻¹.

(±)-Diethyl 2-(3-hexylundecan-2-yl)malonate: According to the generalprocedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg, 2 μmol, 0.01 equiv.),2-hexyldecanoic acid (52 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), 0.5 mL of DMF and 34 W Blue LED (instead of 26 Wfluorescent light bulb) were used. The product was isolated by flashchromatography (10% ethyl acetate/hexane) as a pale yellow oil (42 mg,53%). ¹H NMR (500 MHz, CDCl₃) 4.21-4.16 (m, 4H), 3.34 (d, J 10.5 Hz,1H), 2.46-2.38 (m, 1H), 1.36-1.17 (m, 30H), 1.00-0.94 (m, 1H), 0.88 (t,J=7.01 Hz, 6H), 0.81 (t, J=7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ169.12, 168.97, 61.16, 56.63, 39.69, 35.09, 31.93, 31.89, 31.79, 30.32,30.09, 29.96, 29.75, 29.64, 29.59, 29.38, 29.31, 28.06, 28.02, 27.42,27.39, 22.70, 14.13, 11.61; HRMS (ESI) m/z calcd for C₂₄H₄₆NaO₄[(M+Na)⁺]421.3294, found 421.3293. IR (film) 2924, 2855, 1757, 1733,1175, 1032 cm⁻¹.

(t)-Diethyl 2-(14 (3r, 5r, 7r)-adamantan-1-yl)ethyl)malonate: Accordingto the general procedure. Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg, 2 μmol,0.01 equiv.), 1-adamantanecarboxylic acid (36 mg, 0.2 mmol, 1.0 equiv),diethyl ethylidenemalonate (37.7 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0mg, 0.24 mmol, 1.2 equiv), 0.5 mL of DMF and 34 W Blue LED (instead of26 W fluorescent light bulb) were used. The product was isolated byflash chromatography (10% ethyl acetate/hexane) as a pale yellow oil (60mg, 93%). ¹H NMR (500 MHz, CDCl₃) δ 4.21-4.14 (m, 4H), 3.57 (d, J=5.5Hz, 1H), 2.09-2.04 (m, 1H), 1.98-1.95 (m, 3H), 1.69-1.67 (m, 3H),1.61-1.59 (m, 3H), 1.53-1.47 (m, 6H), 1.27 (q, J=7.0 Hz, 6H), 0.98 (d,J=7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.38, 169.79, 61.32, 60.89,51.83, 43.08, 39.36, 37.02, 35.23, 28.61, 14.09, 14.05, 10.40; HRMS(ESI) m/z calcd for C₁₉H₃₀NaO₄ [(M+Na)⁺] 345.2042, found 345.2024. IR(film) 2901, 2848, 1728, 1218, 1148, 1137, 1031 cm⁻¹.

(±)-Diethyl2-(3-((tert-butoxycarbonyl)amino)-4-phenylbutan-2-yl)malonate: Accordingto the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg, 2 μmol,0.01 equiv.), Boc-Phe-OH (53.0 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (15% ethyl acetate/hexane) as a pale yellow oil(77 mg, 94%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers: δ7.29-7.25 (m, 2H), 7.21-7.15 (m, 3H), 4.49 (d, J=9.5 Hz, 0.43H),4.32-3.98 (m, 5H), 3.86-3.72 (m, 0.57H), 3.51-3.46 (m, 0.55H), 3.39-3.33(m, 0.45H), 2.99-2.95 (m, 0.6H), 2.81-2.73 (m, 0.81), 2.66-2.61 (m,0.6H), 2.50-2.39 (m, 1H), 1.32-1.19 (m, 15H), 1.15 (d, J=6.5 Hz,0.1.7H), 0.95 (d, J=7.0 Hz, 1.3H); ¹³C NMR (125 MHz, CDCl₃) mixture ofdiastereomers: δ 169.67, 169.01, 168.43, 155.56, 155.34, 138.03, 137.97,129.41, 129.17, 128.51, 128.48, 126.48, 79.30, 79.21, 61.60, 61.48,61.46, 61.43, 55.65, 55.26, 54.28, 52.81, 39.93, 39.08, 37.18, 35.76,28.36, 15.12, 14.20, 14.18, 14.12, 11.15; HRMS (ESI) m/z calcd forC₂₂H₃₄NO₆ [(M+H)⁺] 408.2386, found 408.2388. IR (film) 2978, 1704, 1365,1165, 1026, 699 cm⁻¹.

(±)-Diethyl2-(6-amino-3-((tert-butoxycarbonyl)amino)-6-oxohexan-2-yl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy) (2.2 mg, 2μmol, 0.01 equiv.), Boc-Gln-OH (49 mg, 0.2 mmol, 1.0 equiv), diethylethylidenematonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (60% ethyl acetate/hexane) as a pale yellowsolid (65 mg, 84%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers: δ6.35 (s, 0.5H), 6.14 (s, 0.5H), 5.40 (s, 1H), 4.76 (d, J=10.0 Hz, 0.5H),4.46 (d, J=10.5 Hz, 0.5H), 4.23-4.17 (m, 4H), 3.87-3.81 (m, 0.5H),3.64-3.59 (m, 0.5H), 3.44 (d, J=6.51 Hz, 0.5H), 3.20 (d, J=10.0 Hz,0.5H), 2.46-2.34 (m, 1H), 2.29-2.24 (m, 2H), 2.02-1.96 (m 0.5H),1.83-1.77 (m, 2H), 1.63-1.55 (m, 0.5H), 1.42 (s, 9H), 1.29-1.24 (m, 6H),1.06 (d, J=7.0 Hz, 1.5H), 0.91 (d, J=7.0 Hz, 1.5H); ¹³C NMR (125 MHz,CDCl₃) mixture of diastereomers: δ 175.61, 175.55, 169.42, 168.91,168.81, 168.52, 156.35, 156.30, 79.56, 79.49, 61.64, 61.53, 61.48,61.47, 55.53, 54.25, 53.49, 51.50, 37.90, 36.96, 32.96, 32.65, 29.75,29.28, 28.39, 28.36, 14.73, 14.13, 14.09, 14.03, 11.14: HRMS (ESI) m/zcalcd for C₈H₃₃N₂O₇ [(M+H)⁺] 389.2288, found 389.2296. IR (film) 3347,2978, 1670, 1165, 1026.735 cm⁻¹.

(±)-5-Benzyl 1,1-diethyl3-((tert-butoxycarbonyl)amino)-2-methylpentane-1,1,5-tricarboxylate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 ng,2 μmol, 0.01 equiv.), Boc-Glu(OBzl)-OH (67 mg, 0.2 mmol, 1.0 equiv),diethyl ethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0mg, 0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product wasisolated by flash chromatography (20% ethyl acetate/hexane) as a paleyellow oil (89 mg, 93%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers: 7.38-7.31 (m, 5H), 5.15-5.08 (m, 2H), 4.52 (d, J=10.0 Hz,0.4H), 4.31 (d, J=10.5 Hz, 0.4H), 4.22-4.16 (m, 4.2H), 3.86-3.74 (m,0.5H), 3.62-3.49 (m, 0.5H), 3.42 (d, J=7.0 Hz, 0.5H), 3.28 (d, J=10.0Hz, 0.5H), 2.50-2.34 (m, 3H), 2.03-1.96 (m, 0.5H), 1.85-1.74 (m, 1H),1.65-1.60 (m, 0.5H), 1.41 (m, 5H), 1.40 (s, 4H), 1.27 (qd, J=7.0 Hz,J=3.0 Hz, 6), 1.05 (d, J=7.0 Hz, 1.6H), 0.89 (d, J=7.0 Hz, 1.4H); ¹³CNMR (125 MHz, CDCl₃) mixture of diastereomers: δ 173.23, 173.20, 169.45,168.82, 168.78, 168.38, 155.70, 155.51, 135.90, 135.89, 128.56, 128.24,128.21, 128.20, 79.37, 79.26, 66.37, 66.34, 61.56, 61.43, 61.37, 55.41,54.26, 53.59, 51.52, 37.87, 36.83, 31.47, 31.02, 28.70, 28.35, 28.32,28.14, 14.69, 14.10, 14.06, 14.01, 11.12; HRMS (ESI) n/z calcd forC₂₅H₃₈NO₈ [(M+H)⁺] 480.2597, found 480.2604. IR (film) 2978, 1727, 1710,1161, 1026, 698 cm⁻¹.

(±)-Diethyl2-(3-((tert-butoxycarbonyl)amino)-5-(methylthio)pentan-2-yl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Boc-Met-O (50.0 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (20% ethyl acetatehexane) as a pale yellow oil(74 mg, 94%). ¹H NMR (500 MHz CDCl₃) mixture of diastereomers: δ 4.56(d, J=9.5 Hz, 0.5H), 4.31 (d, J=10.5 Hz, 0.3H), 4.23-4.17 (m, 4.2H),3.92-3.87 (m 0.4H), 3.68-3.63 (m, 0.6H), 3.42 (d, J=7.0 Hz, 0.6H), 3.29(d, J=10.0 Hz, 0.4H), 2.59-1.67 (m, 8H), 1.43 (s, 5H), 1.42 (s, 4H),1.29-1.25 (m, 6H), 1.05 (d, J=7.0 Hz, 1.7H), 0.89 (d, J=7.0 Hz, 1.3H);¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers: δ 169.53, 168.90,168.45, 155.74, 155.58, 79.46, 79.32, 61.64, 61.53, 61.46, 55.49, 54.33,53.58, 51.41, 37.66, 36.80, 34.02, 33.02, 31.16, 30.85, 28.42, 28.39,15.76, 15.74, 14.81, 14.17, 14.14, 14.08, 11.20; HRMS (ESI) m-z calcdfor C₁₈H₃₃NNaO₆S [(M+Na)⁺] 414.1926, found 414.1940. IR (film) 2978,1715, 1366, 1168, 1031 cm⁻¹.

(±)-Diethyl2-(4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)butan-2-yl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF (2.2 mg,2 μmol, 0.01 equiv.), Boc-Ser(Bzl)-OH (59 mg, 0.2 mmol, 1.0 equiv),diethyl ethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv). K2HPO₄ (42.0mg, 0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product wasisolated by flash chromatography (25% ethyl acetate/hexane) as a paleyellow oil (83 mg, 94%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers: δ 7.36-7.27 (m, 5H), 4.94 (d, J=9.5 Hz, 0.5H), 4.68 (d,J=9.5 Hz, 0.5H), 4.53-4.46 (m, 2H), 4.23-4.14 (m, 4H), 4.04-3.92 (m,0.5H), 3.78-3.75 (m, 0.5H), 3.63-3.55 (m, 1.5H), 3.50-3.46 (m, 1H), 3.41(d, J=9.0 Hz, 0.5H), 2.61-2.56 (m, 1H), 1.43 (s, 4.3H), 1.42 (s, 4.7H),1.26 (td, J=7.0 Hz, J=2.51 Hz, 6H), 1.05 (d, J=7.0 Hz, 1.6H), 0.96 (d,J=7.0 Hz, 1.4H); ¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers: δ169.76, 168.99, 168.88, 168.76, 155.80, 155.61, 138.11, 128.50, 128.49,127.81, 127.76, 127.69, 79.45, 79.35, 73.29, 73.06, 70.96, 70.20, 61.48,61.38, 61.26, 55.12, 53.89, 53.50, 51.23, 34.94, 34.91, 28.46, 14.41,14.21, 14.18, 14.14, 12.31; HRMS (ESI) m/z calcd for C₂₃H₃₆NO₇ [(M+H)⁺]438.2492, found 438.2496. IR (film) 2978, 1715, 1164, 1028, 698 cm⁻¹.

(±)-Diethyl2-(3-((tert-butoxycarbonyl)amino)-4-(H-indol-3-yl)butan-2-yl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Boc-Trp-OH (61 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (20% ethyl acetate/hexane) as a pale yellowsolid (51 mg, 57%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers: δ8.02 (br, 1H), 7.60 (dd, J=17.5 Hz, J=8.0 Hz, 1H), 7.60 (dd, J=8.0 Hz,J=3.5 Hz, 1H), 7.20-7.16 (m, 1H), 7.13-7.05 (m, 2H), 4.59 (d, J=9.5 Hz,0.3H), 4.41 (d, J=9.5 Hz, 0.3H), 4.30-428 (m, 0.4H), 4.22-4.15 (m,4.5H), 3.95 (br, 0.5H), 3.54 (d, J=6.5 Hz, 0.5H), 3.39 (d, J=10.0 Hz,0.5H), 3.10-3.06 (m, 0.5H), 2.95-2.78 (m, 1.5H), 2.62-2.56 (m, 0.5H),2.48 (q, J=7.0 Hz, 0.5H), 1.35-1.33 (m, 6H), 1.29-1.17 (m, 9H),1.10-1.03 (m, 1.5H), 0.97 (d, J=7.0 Hz, 1.5H); ¹³C NMR (125 MHz, CDCl₃)mixture of diastereomers: δ 169.80, 169.20, 169.12, 168.65, 155.85,155.63, 136.57, 136.27, 128.07, 127.82, 127.54, 122.78, 122.63, 122.46,121.97, 121.88, 119.40, 119.30, 118.86, 118.69, 111.98, 111.47, 111.25,79.31, 79.11, 61.57, 61.51, 61.45, 55.77, 5456, 54.16, 52.07, 36.86,36.42, 35.76, 28.36, 27.73, 15.15, 14.18, 14.14, 14.05, 11.09; HRMS(ESI)m/z calcd for C₂₄H₃₅N₂O₆ [(M+H)⁺] 447.2495, found 447.2498. IR(film) 3387, 2978, 1721, 1169, 1027, 741 cm⁻¹.

(±)-Diethyl2-(1-(1-(((benzyloxy)carbonyl)glycyl)pyrrolidin-2-yl)ethyl)malonate:According to the general procedure, Ir[dF(CFI)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 mol, 0.01 equiv.), Z-Gly-Pro (61.1 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.20 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg,0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product wasisolated by flash chromatography (20% ethyl acetate/hexane) as a paleyellow solid (79 mg, 88%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 7.36-7.229 (m, 5H), 5.80-5.59 (m, 1H),5.14-5.09 (m, 2H), 4.31-4.28 (m, 0.4H), 4.23-4.13 (m, 4H), 4.09-4.00 (m,0.6H), 4.00 (d, J=4.0 Hz, 0.15H), 3.96 (dd, J=7.01 z, J=7.01 Hz,0.5511), 3.91 (q, J=4.5 Hz, 0.61), 3.87 (d, J=4.0 Hz, 0.3H), 3.81 (d,J=4.0 Hz, 0.2H), 3.78 (q, J=4.5 Hz, 0.2H), 3.64 (q, J=9.5 Hz, 0.4H),3.50-3.47 (m, 0.6H), 3.46-3.44 (m, 0.4H), 3.32-3.18 (m, 1.6H), 2.70-2.65(m, 1H), 2.10-1.76 (m, 4H), 1.29-1.19 (m, 6H), 1.01 (d, J=7.0 Hz, 0.2H),0.95 (d, J=6.5 Hz, 1.3H), 0.92 (d, J=7.0 Hz, 0.2H), 0.88 (d, J=7.0 Hz,1.31); ¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers and rotamers: δ169.01, 168.84, 168.67, 168.46, 168.37, 168.11, 168.05, 167.92, 167.70,167.58, 156.25, 156.21, 136.56, 136.54, 128.55, 128.12, 128.03, 66.86,62.04, 62.00, 61.81, 61.79, 61.51, 61.38, 61.36, 61.07, 60.26, 60.05,59.05, 55.70, 55.09, 53.30, 46.93, 46.82, 46.39, 46.06, 43.78, 43.48,43.37, 37.25, 36.78, 36.35, 36.16, 29.14, 27.60, 24.47, 23.84, 22.73,22.32, 1426, 14.17, 14.11, 14.05, 13.38; HRMS (ESI) m/z calcd forC₂₃H₃₃N₂O₇ [(M+H)⁺] 1449.2288, found 449.2278. IR (film) 2976, 1721,1647, 1243, 1028, 698 cm⁻¹.

(±)-Diethyl2-(3-(2-(((benzyloxy)carbonyl)amino)acetamido)-4-phenylbutan-2-yl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Z-Gly-Phe (71.3 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 1.0 mL of DMF were used. The product was isolatedby flash chromatography (20% ethyl acetate/hexane) as a pale yellowsolid (90 mg, 90%), 11 NMR (500 MHz, CDCl₃) mixture of diastereomers androtamers: δ 7.37-7.30 (m, 5H), 7.27-7.24 (m, 2H), 7.21-7.17 (m, 1H),7.16-7.12 (m, 2H), 6.44 (d, J=9.0 Hz, 0.6H), 5.92 (d, J=8.0 Hz, 0.4H),5.21 (br, 1H), 5.13 (s, 2H), 4.47 (q, J=8.0 Hz, 0.4H), 4.24-4.14 (m,4.6H), 3.76-3.67 (m, 2H), 3.50 (d, J=6.5 Hz, 0.6H), 3.29 (d, J=9.5 Hz,0.41), 2.93-2.89 (m, 0.6H), 2.84-2.80 (m, 0.4H), 2.75-2.71 (m, 1H),2.53-2.41 (m, 1H), 1.27-1.22 (m, 6H), 1.14 (d, J=6.5 Hz, 1.7H), 0.94 (d,J=7.0 Hz, 1.3H); ¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers androtamers: δ 169.24, 168.99, 168.82, 168.48, 168.38, 156.73, 156.51,137.73, 137.57, 136.27, 136.21, 129.24, 128.97, 128.60, 128.57, 128.50,128.48, 128.29, 128.24, 128.03, 126.62, 126.58, 67.12, 67.07, 61.72,61.64, 61.53, 61.43, 55.59, 53.95, 53.59, 51.67, 44.62, 44.47, 39.32,38.14, 36.23, 35.91, 15.01, 14.12, 14.07, 14.06, 11.14; HRMS (ESI) m/zcalcd for C₂₇H₃₅N₂O₇ [(M+H)⁺] 449.2444, found 449.2420. IR (film) 3321,2980, 1722, 1230, 1027, 733, 697 cm⁻¹.

(±)-Diethyl 2-(1-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)ethyl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]2(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Z-Pro-OH (50.0 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (20% ethyl acetatehexane) as a pale yellow oil(72 mg, 92%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers androtamers: 6 7.42-7.29 (m, 5H), 5.21-5.03 (m, 2H), 4.20-3.84 (m, 5H),3.69-3.36 (m, 2H), 3.24-3.17 (m, 1H), 2.80-2.73 (m, 0.6H), 2.68-2.63 (m,0.4H), 2.02-1.72 (m, 4H), 1.28-1.18 (m, 6H), 0.96-0.87 (m, 3H); ¹³C NMR(125 MHz, CDCl₃) mixture of diastereomers and rotamers: δ 169.05,168.93, 168.87, 168.81, 168.71, 168.56, 168.47, 155.95, 155.85, 155.70,155.27, 136.87, 136.81, 136.72, 136.65, 128.44, 128.20, 128.14, 127.92,127.83, 127.77, 67.11, 66.79, 61.70, 61.46, 61.23, 60.56, 60.47, 59.96,55.58, 55.13, 55.00, 54.50, 47.95, 47.66, 47.26, 46.76, 37.13, 37.05,29.15, 28.78, 28.27, 28.16, 24.41, 23.79, 23.65, 23.19, 14.22, 14.12,14.06, 14.02, 13.87, 13.68, 13.48; HRMS (ESI) m/z calcd for C₂₁H₃₀NO₆[(M+H)⁺] 392.2073, found 392.2066. IR (film) 2977, 1695, 1405, 1096,1027, 697 cm⁻¹.

(±)-Diethyl 2-(1-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Boc-Pro-OH (43.0 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (20% ethyl acetate/hexane) as a pale yellow oil(69 mg, 97%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers androtamers: δ 4.22-4.11 (m, 4H), 3.97-3.30 (m, 3H), 3.17-3.12 (m, 0.55H),3.11-3.06 (m, 0.45H), 2.75-2.71 (m, 0.83H), 2.60-2.53 (m, 0.17H),2.00-1.67 (m, 4H), 1.46 (s, 9H), 1.28-1.23 (m, 6H), 0.94-0.88 (m, 3H);¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers and rotamers: δ168.88, 168.73, 168.36, 155.43, 155.20, 154.79, 79.77, 79.07, 61.29,61.12, 60.52, 60.26, 59.91, 55.52, 54.74, 54.00, 47.72, 47.14, 46.95,46.81, 37.00, 36.77, 28.45, 28.42, 24.37, 23.77, 23.48, 23.26, 14.08,14.02; HRMS (ESI) m/z calcd for C₁₈H₃₂NO₆ [(M+H)⁺] 358.2230, found358.2235. IR (film) 2975, 1729, 1689, 1381, 1365, 1162, 1105, 1030, 773cm⁻¹.

(±)-Diethyl 2-(I-(1-benzoylpyrrolidin-2-yl)ethyl)malonate: According tothe general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (5.5 mg, 5 μmol, 0.01equiv.), Benzoyl-L-proline (110 mg, 0.5 mmol, 1.0 equiv.), K₂HPO₄ (105mg, 0.6 mmol, 1.2 equiv.), diethyl 2-ethylidenemalonate (93 mg, 0.5mmol, 1.0 equiv.) and DMF (1.25 mL) were used. The product was isolatedby flash chromatography (30% ethyl acetate in hexanes) as a pale yellowoil (150 mg, 83%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers androtamers: δ 7.56-7.48 (m, 2), 7.44-7.34 (m, 3H), 4.57 (td, J=8.0, 3.0Hz, 0.4H), 4.48-4.42 (m, 0.6), 4.30-4.10 (m, 4H), 3.82 (d, J=10.0 Hz,0.4H), 3.54-3.47 (m, 1H), 3.44-3.36 (m, 1.6H), 3.02-2.93 (m, 0.6H),2.80-2.71 (m, 0.4H), 2.26-2.17 (m, 0.4H), 2.20-1.56 (m, 3.6H), 1.29-1.19(m, 6H), 1.01-0.99 (m, 3H): ¹³C NMR (125 MHz, CDCl₃) mixture ofdiastereomers and rotamers: δ 171.51, 170.63, 169.34, 169.20, 168.88,168.68, 136.88, 136.82, 130.24, 130.14, 128.16, 128.10, 127.69, 127.61,61.37, 61.25, 61.21, 61.17, 59.92, 59.05, 55.48, 51.99, 50.81, 37.31,35.29, 29.42, 26.82, 25.40, 25.12, 14.12, 14.09, 14.02, 14.00, 12.97,12.49; HRMS (ES) m/z calcd for C₂₀H₂₈NO₅ [(M+H)⁺] 362.1962, found362.19642. IR (film) 2977, 1747, 1726, 1627, 1394, 1265, 1174, 1150,1027, 792, 70) cm⁻¹.

(±)-Diethyl 2-(1-(1-(tert-butoxycarbonyl)piperidin-2-yl)ethyl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Boc-Pip-OH (45.8 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), K₂HPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (20% ethyl acetate/hexane) as a pale yellow oil(70 mg, 94%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers:4.26-3.95 (m, 6H), 3.43 (d, J=4.5 Hz, 1H), 2.79-2.68 (m, 2H), 1.80-1.78(m, 0.4H), 1.71-1.69 (m, 0.6), 1.58-1.49 (in, 5H), 1.44 (s, 9H),1.30-1.24 (m, 6H), 1.07 (d. J=6.5 Hz, 1.3H), 0.99 (d, J=7.0 Hz, 1.7H);¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers: δ 169.87, 169.24,168.52, 168.24, 155.16, 155.14, 79.50, 79.39, 61.49, 61.39, 61.17,60.91, 53.37, 53.14, 31.97, 31.70, 28.49, 28.45, 26.18, 25.39, 19.04,18.89, 14.21, 14.14, 14.11, 13.80, 12.90; HRMS (ESI) m/z calcd forC₁₉H₃₃NNaO₆ [(M+Na)⁺] 394.2206, found 394.2192. IR (film) 2977, 2935,1687, 1150, 1028, 866 cm⁻¹,

(±)-Diethyl 2-(1-(4-(ter-butoxycarbonyl)morpholin-3-yl)ethyl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF (2.2 mg,2 μmol, 0.01 equiv.). Boc-Morph-OH (46.2 mg, 0.2 mmol, 1.0 equiv),diethyl ethylidenemalonate (37.3 mg, 0.20 mmol, 1.0 equiv), K₂HPO₄ (42.0mg, 0.24 mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product wasisolated by flash chromatography (20% ethyl acetate/hexane) as a paleyellow oil (71 mg, 95%). ¹H NMR (500 MHz, CDCl₃) mixture ofdiastereomers: δ 4.23-4.10 (m, 4), 4.01-3.78 (m, 4H), 3.51-3.44 (m, 3H),3.13-3.03 (m, 1H), 2.93-2.85 (m, 1H), 1.46 (s, 4.5H), 1.45 (s, 4.5H);1.30-1.25 (m, 6H), 1.16 (d, J=7.0 Hz, 1.5H), 1.05 (d. J=7.0 Hz, 1.5H);¹³C NMR (125 MHz, CDCl₃) mixture of diastereomers: δ 168.83, 168.26,168.22, 154.76, 154.59, 80.28, 67.21, 67.14, 61.48, 61.27, 60.97, 52.90,52.66, 31.21, 28.40, 28.36, 14.21, 14.16, 14.14, 14.09, 13.67, 12.80;HRMS (ESI) m/z calcd for C₁₈H₃₁NNaO₇ [(M+Na)⁺] 396.1998, found 396.1995.IR (film) 2978, 1729, 1690, 1103, 866 cm⁻¹.

(±)-Diethyl 2-(1-((tert-butoxycarbonyl)amino)propan-2-yl)malonate:According to the general procedure, Ir[dF(CF₃)ppy)]₂(dtbbpy)PF₆ (2.2 mg,2 μmol, 0.01 equiv.), Boc-Gly-OH (35.0 mg, 0.2 mmol, 1.0 equiv), diethylethylidenemalonate (37.3 mg, 0.2 mmol, 1.0 equiv), KHPO₄ (42.0 mg, 0.24mmol, 1.2 equiv), and 0.5 mL of DMF were used. The product was isolatedby flash chromatography (25% ethyl acetate/hexane) as a pale yellow oil(60 mg, 94%). ¹H NMR (500 MHz, CDCl₃) mixture of diastereomers: δ 4.71(s, 1H), 4.20 (qd, J=7.01 Hz, J=2.0 Hz, 4H), 3.31 (d, J=7.5 Hz, 1H),3.22-3.12 (m, 2H), 2.48-2.43 (m, 1H), 1.43 (s, 9H), 1.27 (d, J=7.5 Hz,6H), 1.01 (d, J=7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) mixture ofdiastereomers: δ 168.78, 168.56, 155.96, 79.21, 61.41, 61.35, 55.02,44.18, 34.08, 28.37, 15.52, 14.09, 14.06; HRMS (ESI) m/z calcd forC₁₅H₂₇NNaO₆ [(M+Na)⁺] 1340.1736, found 340.1739, IR (film) 2978, 1714,1515, 1246, 1164, 1030 cm⁻¹.

Various embodiments of the invention have been described in fulfillmentof the various objectives of the invention. It should be recognized thatthese embodiments are merely illustrative of the principles of thepresent invention. Numerous modifications and adaptations thereof willbe readily apparent to those skilled in the art without departing fromthe spirit and scope of the invention.

The invention claimed is:
 1. A method of intramolecular peptidecyclization comprising: providing a reaction mixture including a peptidecomprising a C-terminal residue and a Michael acceptor functionalizedN-terminal residue; and coupling the C-terminal residue with the Michaelacceptor functionalized N-terminal residue via a mechanism includingdecarboxylation.
 2. The method of claim 1, wherein the peptide comprisesat least 3 residues.
 3. The method of claim L wherein decarboxylationoccurs subsequent to formation of a carboxyl radical at the C-terminalresidue.
 4. The method of claim 3, wherein carboxyl radical formation isinitiated by a single electron transfer (SET) process.
 5. The method ofclaim 4, wherein the SET process is oxidative.
 6. The method of claim 4,wherein the SET process is reductive.
 7. The method of claim 3, whereinan α-amino radical is formed by the decarboxylation at the C-terminalresidue.
 8. The method of claim 7, wherein the α-amino radical undergoesconjugate addition with the Michael acceptor functionalized N-terminalresidue.
 9. The method of claim 4, wherein the reaction mixture furthercomprises catalyst for initiating the SET process.
 10. The method ofclaim 9, wherein the catalyst is transition metal catalyst.
 11. Themethod of claim 9, wherein the catalyst is photoredox catalyst.
 12. Themethod of claim 11, wherein the photoredox catalyst is an iridiumcomplex.
 13. The method of claim 12, wherein the iridium complex isheteroleptic.
 14. The method of claim 13, wherein the heterolepticiridium complex is selected from the group consisting ofIr[dF(CF₃)ppy]₂(dtbbpy)⁺ and Ir(ppy)₂(dtbbpy)⁺.
 15. The method of claim9, wherein the reaction mixture further comprises co-catalyst forhydrogen atom transfer to the intramolecular cyclized peptide.
 16. Themethod of claim 15, wherein the co-catalyst comprises one or more arylthiols.
 17. The method of claim 4, wherein the reaction mixture furthercomprises base.
 18. The method of claim 9, wherein the catalyst alsoreduces an α-acyl radical formed during intramolecular cyclization ofthe peptide.
 19. The method of claim 4, wherein the SET process isinitiated electrochemically.